Formatting, Assembling, and

Submitting
the New Drug Application (NDA)

Agnimitra Dinda

School of Pharmaceutical Sciences

Bhubaneswar
INDIA
Introduction:
• The new drug application (NDA) is a
critical component in the drug
approval process. The U.S. Food and
Drug Administration (FDA) requires
drug sponsors to submit an NDA for
review before a new pharmaceutical
can be approved for marketing and
sale in the U.S.
• The NDA contains clinical and
nonclinical test data and analyses,
drug chemistry information, and
descriptions of manufacturing
FDA Guidelines:

• NDA shares many common

elements with the Common
Technical Document (CTD)
developed by the International
Conference on Harmonization (ICH)
in order to streamline submissions
for registration in all three ICH
regions: the U.S., the European
Union, and Japan.
A list of the current FDA guidelines:
• Guideline on Formatting, Assembling, and
Submitting New Drug and Antibiotic
Applications
• Guideline for the Format and Content of the
Summary for New Drug and Antibiotic
Applications
• Guideline for the Format and Content of the
Nonclinical/Pharmacology/Toxicology Section
of an Application
• Guideline for the Format and Content of the
Human Pharmacokinetics and Bioavailability
Section of an Application
• Guideline for the Format and Content of the
Microbiology Section of an Application
• Guideline for the Format and Content of the
Clinical and Statistical Sections of New Drug
Applications
• Guideline for the Format and Content of the
Chemistry, Manufacturing, and Controls
Section of an Application
• Guideline for Submitting Supporting
Documentation in Drug Applications for the
Manufacture of Drug Substances
• Guideline for Submitting Samples and
Analytical Data for Methods Validation
• Guideline for Submitting Documentation for
Packaging for Human Drugs and Biologics
• Guideline for Submitting Documentation for
the Stability of Human Drugs and Biologics.
NDA Contents:
1. Index
2. Labeling (±)
3. Application Summary
4. CMC and Methods Validation Package
5. Nonclinical Pharmacology andToxicology
6. Human Pharmacokinetics and
Bioavailability
7. Microbiology
8. Clinical data
9. Safety Updates
10. Statistical information
11. Case Report Tabulation
12. Case Report Forms
13: Patent Information
14: Patent Certification
15: Establishment Description (if
applicable)
16: Debarment Certification
17: Field Copy Certification
18: User Fee Cover Sheet (Form FDA-
3397)
19: Financial Disclosure (Form FDA-
3454, Form FDA-3455)
20: 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
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.

• One copy should be bound into the

archival copy. Copies should also be
placed in the review copies of the
clinical, chemistry, and
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.
• 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
NDA Section 4: Chemistry, Manufacturing,
and Controls (CMC):
• 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.
Deficiencies in this section are
common.
NDA Section 5: Nonclinical Pharmacology
and Toxicology:

• The second technical section of the

NDA provides a description or
summary of all animal and in vitro
studies with the drug.
• The table of contents should
clearly identify all studies not
previously submitted to the IND.
It includes:

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 (or cross-
reference the location of the
information in any of the above
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
Present 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)
NDA Section 6: Human Pharmacokinetics
and Bioavailability:
• The first element in this section is a
tabulated summary of studies showing
all in vivo biopharmaceutic studies
performed. Include a summary of data
and overall conclusions.
• Peak concentration (Cmax)
• Area under the curve (AUC)
• Time to reach peak concentration
(tmax)
• Elimination constant
• Distribution volume (Vd)
• Plasma and renal clearance
• Urinary excretion
NDA Section 7: Microbiology:

• 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 on the effects of the
antimicrobial drug on the
microorganism are critical in
establishing the new drug’s
effectiveness.
NDA Section 8: Clinical Data:
1. A table of all studies
2. Full clinical trial reports of all controlled
studies in the following order:
• a. Completed studies (U.S. studies followed
by non-U.S. studies and any published trials)
• b. Ongoing studies with interim results (same
order as above)
• c. Incomplete or discontinued studies (same
order as above)
3. Full reports of dose-comparison concurrent
control studies, followed by those for “no-
treatment” concurrent control, active control
studies, and historical control 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
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
NDA Section 11: Case Report Form
Tabulations

• 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.
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.
The Common Technical Document developed by
ICH is organized into
well-defined modules.
As noted above, 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 required to get the NEW DRUG
APPROVAL

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