NEW DRUG APPLICATION

(NDA)

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 INTRODUCTION
 It is an application submitted to USFDA for permission to market newly

develop product.
 Justification of NDA:

1. Is the drug safe and effective for its proposed use?

2. Do the benefits of the drug outweigh the risks?

3. Is the drug’s proposed labeling (the Prescribing Information)

appropriate and complete?

4. Are the methods used to manufacture the drug—and the process

controls used to maintain the drug’s quality— adequate to preserve the
drug’s identity, strength, quality, and purity?
 All regulations guidance and forms are provided by USFDA as
Title 21 of Code of Federal Regulation (21 CFR).

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 DEFINITION
 Application: It means an application as per 21 CFR 314.50
including all amendments and supplement as described in
section 505.

 Original application: It is one which is a pending

application for which FDA has never issued a complete
postpones/Approval letters OR it may be a application
submitted after withdrawal or rejection.

 Approval letter: It is written communication to an

applicant from FDA approving an application or an
abbreviated application.

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 DEFINITION
 Drug substance: It means an active ingredient, that is

intended for pharmacological activity or other direct effect

in the diagnosis, cure , mitigation, treatment or prevention
of disease or to affect the structure or any function of
human body but it does not include intermediates, used in
the synthesis of such ingredients.

 Prodrug: It is chemically modified inert drug precursor

which upon biotransformation liberates pharmacologically

active parent compound.

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 DEFINITION
 Drug product: A finished dosage form that contains a drug

substance, generally but not necessarily in association with

one or more ingredient.

 Complete response letter: It means a written

communication to an applicant from FDA describing all of its
deficiency that the agency had identified in an application
that must be satisfactory addressed before it can be
approved.

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 DEFINITION

 Resubmission: It is an application submitted by the

applicant with all materials needed to fully addressed all the

deficiency identified in the complete response letter.

 Generic drug product: It is that drug product which is free

from any patent or copyright protection.

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 CONTENT OF AN APPLICATION
 All application including abbreviated applications and
supplements to approved applications must be formally
submitted and to contain the information required in 21
CFR 314.50.

 Two copies of application are needed: an ARCHIVAL and a

REVIEW copy.

 An application for a new chemical entity will generally

contain: Signed FDA 356h form, an index, a summary,
five or six technical sections, case report tabulations of
patient data, case report forms, drug samples and
labeling.

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 APPLICATION FORMAT
 The NDA regulations require the submission of :

1. Archival copy: This is a complete copy of an application

submission and is intended to serve as a reference source for
FDA reviewers to locate information not contained in the
review copy, as a reference source for other FDA officials.

After approval, the archival copy is retained by the FDA and

serves as the sole file copy of the approved application.

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 APPLICATION FORMAT
2.Review copy: The review copy of an application is divided into
five (or six) sections containing the technical and scientific
information required by FDA reviewers. Each of the technical
sections of the review copy is separately bound.
With the review copy, each reviewer should be provided with
the following
- A copy of the cover letter.
- A copy of the application form (FDA 356h).
- A copy of the overall summary.
- A copy of the entire application
- An index to the specific review section.
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 ASSEMBLING THE APPLICATION

FOLDERS

Documents Folder color Folder

number
Archival copy Blue FD 2626
Chemistry, manufacturing and Red FD 2626a
control section
Nonclinical pharmacology and Yellow FD 2626b
toxicological section
Human pharmacokinetics and Orange FD 2626c
bioavailability section
Microbiological section White FD 2626d
Clinical data section Light brown FD 2626e
Statistical section Green FD 2626f
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 PAPER SIZE AND BINDING
 All application must be bound on the left side of the page using

the United States standard size loose4-leaf page (81/2” X 11”).

 Both sides of the page may be used for the presentation of

information and data, provided:

1. Information and data on both sides are not obscured in the

binding.

2. Legibility is not impaired because of bleeding of the copy

through the page.

3. Pages are in correct order and accurately numbered.

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 PAGINATION

 Paging and indexing permit rapid access to the

entire submission.

 It is important that all pages in the application be

numbered and that the numbering of the review

copy pages be the same as the numbering of the

corresponding pages in the archival copy.

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 VOLUME SIZE AND IDENTIFICATION
 Volumes submitted in hard copy should be no more than 2 inches

thick.

 The front cover of each volume should have proper information:

name of applicant, drug and NDA number (if previously assigned),

clearly written in waterproof marking pen or on typed, stick-on

labels.

 Preprinted in lower right hand corner of each jacket cover is the

legend. “THIS SUBMISSION: VOL.____OF_____VOLS”. The blanks

should be filled in by the applicant to identify the specific volume

and the total number of volume submitted.

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 PACKING CARTON
 The box size of 14” X 12’’ X 9 ½” is recommended for shipment of

application to FDA.
 An exterior label should indicate the contents by applicant’s

name, drug name and volume numbers.

 It is also important to identify which cartons contain archival copy

and which the review copy.

 Full application should sent to:
Food and Drug Administration
Office of Drug Evaluation and Review
Central Document Room
Park Building, Room 214
12420 Parklawn Drive
Rockville, MD 20852
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SUPPLEMENTS, AMENDMENTS and
POSTMARKETING REPORTS

 The submission format for amendments to pending

applications and supplements to approved applications will
be the same as an original application.

 Post marketing reports of adverse drug experience,

including the 15 day “alert reports” and the periodic drug
experience reports, should be submitted, unbound in
duplicate.

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 APPLICATION FORM

1. Applicant information: This section should include the

name, address, telephone and facsimile numbers of the legal
person or entity submitting the application. Only one person
should sign the form.

2. Product description: This section should include all of the

information necessary to identify the product that is the
subject of the submission.

3. Application information: all the information related to the

application form should be included in this section like
application type, type of submission, reason of submission,
number of volumes, etc.
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 APPLICATION FORM

4.Establishment information: This section should include

information on the locations of all manufacturing, packaging and
control sites for both drug substance and drug product.

5.Cross references: This section should contain a list of all License

applications, IND’s, NDA’s, Premarket Approval (PMA’s), Biologics
Master File (BMF’s), Drug Master File (DMF’s), that are referenced
in the current application.

6.Items 1 through 20 on the reverse side of the form constitute a

check list that should be used to indicate the type of information
contained within particular submission.

7.Signature: The form must be signed and dated. Only one person
should sign the from. 17
 INDEX
 An application must contain an index of all the elements of

the application.

 For each element of the application, the index must identify

the volume and page number.

 Each review section must contain an index specific to that

review section.

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 SUMMARY
 An application must contain a summary, usually between 50 to

200 pages in length.

 The summary should be written in approximately the same level

of detail required for publication in recognized scientific and

medical journals.

Information in the summary should be presented in the following

order:

I. Proposed Text of Labelling for the Drug

II. Pharmacological Class, Scientific Rationale, Intended Use and

Potential Clinical Benefits

III. Foreign Marketing History

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IV. Chemistry, Manufacturing and Controls Summary;
 SUMMARY

V. Non-clinical Pharmacology and Toxicology Summary

VI. Human Pharmacokinetic and Bioavailability Summary

VII. Microbiology Summary (if required);

VIII. Clinical Data Summary and Result of Statistical Analysis

IX. Discussion of Benefit/Risk Relationship and Proposed Post

marketing Studies.

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 CHEMISTRY SECTION
 Chemistry, Manufacturing and Controls (CMC) Section:
An application must provide a section on the method of
preparation of the drug substance, the control testing used to
monitor its identity, strength, quality and purity.
 The section must include the following information:
(i) Physical and chemical characteristics;
(ii) Stability;
(iii) Name and address of the manufacturer;
(iv) Manufacturer of the drug substance;
(v) Process controls;
(vi) Drug substance controls;
(vii) Solid-state drug substance forms: relationships to
bioavailability.

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 NONCLINICAL PHARMACOLOGY AND
TOXICOLOGY SECTION
 An application should list all nonclinical studies, with volume
and page numbers, in the application’s table of contents
and replicated at the beginning of this technical section.
 A pharmacology/toxicology summary is required.
 A recommended order for submission of various types of
studies is:
1. Pharmacology Studies;
2. Acute Toxicity Studies;
3. Multiple-dose Toxicity Studies;
4. Special Toxicity Studies;
5. Reproduction Studies;
6. Mutagenicity Studies;
7. Absorption, Distribution, Metabolism, Excretion (ADME)
Studies.
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 HUMAN PHARMACOKINETICS AND
BIOAVAILABILITY SECTION

 Typically, an application should include in the Bio

pharmaceutics Section studies of five general types:

(i) Pilot or Background Studies;

(ii) Bioavailability/Bioequivalence Studies;

(iii) Pharmacokinetic Studies;

(iv) Other In Vivo Studies; and

(v) In Vitro Studies.

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 CLINICAL DATA SECTION
 The application should generally describe the clinical
investigations of the drug, including the following:

(i) a description and analysis of each clinical pharmacology

study of the drug;

(ii) a description and analysis of each controlled clinical study

pertinent to a proposed use of the drug, including the
protocol and a description of the statistical analyses used to
evaluate the study;

(iii) a description of each uncontrolled clinical study, a

summary of the results.
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 CLINICAL DATA SECTION

(iv) a description and analysis of any other data or

information relevant to an evaluation of the safety and
effectiveness of the drug product.

(v) an integrated summary of the data demonstrating

substantial evidence of effectiveness for the claimed
indications;

(vi) a summary and updates of safety information;

(vii) a description and analysis of studies or information related to

abuse of the drug;

(viii) an integrated summary of the benefits and risks of the

drug. 25
 STATISTICAL SECTION

 The application must include a statistical evaluation of clinical

data, including the following:

(i)information concerning the description and analysis of each

controlled clinical study, and the documentation and
supporting statistical analyses used in evaluating the controlled
clinical studies;

(ii)information concerning a summary of information about the

safety of the drug product, and the documentation and
supporting statistical analyses used in evaluating the safety
information.

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 Case Report Forms and Tabulations
 An applicant must submit case reports for:

(i) all patients who died during a clinical study;

(ii) patients who did not complete a study because of any

adverse event.
 An applicant must submit case report tabulations for individual

patients for:

(i) the initial clinical pharmacology studies;

(ii) the adequate and well-controlled clinical studies;

(iii) the safety data.

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 LABELING
 An applicant who submits draft labelling must submit 4

copies. One copy in the archival copy while the other

copies in the chemistry, pharmacology and clinical review
sections.

 An applicant who submits final printed labelling must

submit 12 copies of the final printed labelling. One copy

should be mounted, bound and inserted in the archival copy
while the remaining eleven copies of the final printed
labelling should be mounted, bound and submitted in a
separate jacket clearly labelled “Final Printed Labelling.”
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A good reference discussion..

https://www.excedr.com/blog/new-drug-
application-process