NDA Approval Process.pdf

NDA
( N E W D RU G A PPL I C A T I O N )
Presented By,
Ajay Lunagariya
ACP22PHCE002
M.Pharm Sem-1 (2022-23)
1

Introduction
Definition: The NDA application is the vehicle through which drug sponsors, such as biotech and pharmaceutical
companies, formally propose that the FDA approve a new pharmaceutical for sale and marketing.
• 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 documentation required in an NDA is supposed to tell the drug's whole story, including what happened during
the clinical tests, what the ingredients of the drug are, the results of the animal studies, how the drug behaves in the
body, and how it is manufactured, processed and packaged.
2
NDA (Ajay Lunagariya)

Definitions
❖ Drug: Drug are the substance intended to be used for or in the diagnosis, treatment, mitigation, or prevention
of any disease or disorder in human being or animal.
• All medicines for internal or external use of human beings or animals.
• Such substances (other than food) intended to affect the structure or any function of human body.
• All substances intended for use as components of a drug including empty gelatin capsules.
• Such devices intended for internal or external use in the diagnosis, treatment, mitigation or prevention
of disease or disorder.
❖ New drug: Drug that has not been declared safe and effective by qualified expert under the condition
prescribed, recommended, or suggested in the and that may be new chemical formula or an established drug
prescribed for use in new way.
• A new substance of chemical, biological, or biotechnological origin in bulk or prepared dosage form used
for diagnosis, treatment, mitigation or prevention of any disease or disorder in human or animal which
except during local clinical trial has not been used in the country to any significant extent and during local
clinical trials has not been recognized in the country as effective and safe for the proposed claims.
3

❖ Preclinical Testing
• A pharmaceutical company conducts laboratory and animal studies to show biological activity of the
compound against the targeted disease, and the compound is evaluated for safety. These tests take
approximately three and one-half years.
❖ Investigational NewDrugApplication(IND)
• After completing preclinical testing, the company files an IND with FDA to begin to test the drug in
people. The IND becomes effective if FDA does not disapprove it within 30 days.
• The IND shows results of previous experiments, how, where and by whom the new studies will be
conducted; the chemical structure of the compound; how it is thought to work in the body; any toxic
effects found in the animal studies; and how the compound is manufactured.
• In addition, the IND must be reviewed and approved by the Institutional Review Board where the
studies will be conducted, and progress reports on clinical trials must be submitted at least annually
to FDA.
4

❖ClinicalTrials, Phase I.
These tests take about a year and involve about 20 to 80 normal, healthy
volunteers. The tests study a drug's safety profile, including the safe
dosage range. The studies also determine how a drug is absorbed,
distributed, metabolized and excreted, and the duration of its action.
❖ClinicalTrials, Phase II.
In this phase, controlled studies of approximately 100 to 300 volunteer
patients (people with the disease) assess the drug's effectiveness and take
about two years.
❖ClinicalTrials, Phase III.
This phase lasts about three years and usually involves 1,000 to 3,000
patients in clinics and hospitals. Physicians monitor patients closely to
determine efficacy and identify adverse reactions. 5

❖New Drug Application(NDA).
• Following the completion of all three phases of clinical trials, the company analyzes
all of the data and files an NDA with FDA if the data successfully demonstrate safety
and effectiveness.
• The NDA must contain all of the scientific information that the company has
gathered. NDAs typically run 100,000 pages or more.
• By law, FDA is allowed six months to review an NDA. In almost all cases, the period
between the first submission of an NDA and final FDA approval exceeds that limit;
the average NDA review time for new molecular entities approved in 1992 was 29.9
months.
❖Approval.
• Once FDA approves the NDA, the new medicine becomes available for physicians to
prescribe.
• The company must continue to submit periodic reports to FDA, including any cases
of adverse reactions and appropriate quality-control records. For some medicines,
FDA requires additional studies (Phase IV) to evaluate long-term effects. 6

NEW DRUG APPLICATION
• The New Drug Application (NDA) is an application submitted to FDA for permission
to market a new drug product.
• The goals of the NDA are to provide enough information to permit FDA reviewers to
establish the following:
1. Whether the drug is safe and effective in its proposed use(s), and whether the
benefits of the drug outweigh the risks?
2. Whether the drug’s proposed labeling appropriate, and what should it contain?
3. Are the methods used in manufacturing ( Good Manufacturing Practices ; GMP) of
the drug and the controls used to maintain the drug’s quality adequate to preserve
the drug’s identity, strength, quality, and purity?
7

• To legally gather this data on safety and effectiveness, the maker must first obtain an
Investigational New Drug (IND) designation from FDA.
• The documentation required in an NDA is supposed to tell the drug’s whole story,
including,
1. What happened during the clinical tests,
2. What the ingredients of the drug formulation are,
3. The results of the animal studies,
4. How the drug behaves in the body,
5. How it is manufactured, processed and packaged.
• Once approval of an NDA is obtained, the new drug can be legally marketed starting
that day.
8

OBJECTIVE OF NDA
❖ Whether the drug's proposed labeling (package insert) is appropriate, and what
it should contain.
❖ Whether the drug is safe and effective in its propose use, and whether the benefits of
the drug outweigh the risks .
❖ 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
10

NDA FORM
❖Form FDA-356h. Applicationto market a new drug, biological or
an antibiotic drug for human use.
❖Form FDA 3397. User fee cover sheet.
❖Form FDA 3331. New drug applicationfield report.
❖Impurity in drug substances.
❖Required specification for FDAs IND, and ANDA drug master file
binders.
❖Refusal to file.
11

A) No of copies-
Before 1985- 3 copies & now only 2 copies.
1) Archival copy
• Reference copy for FDA ( i.e. retained by FDA )
• Locate information not contained in review copy
2) Review copy
• Divided in to five or six section containing technical
and scientific information separately bound
• It contains copy of cover letter, application form,
overall summary, index, specific review section
B) Assemblingthe application
1). Folder
• Color folder
Eg. Archival copy - Blue
Chemistry section – Red
• Name of applicant and name of drug product
• NDA no. if known
2). Paper size and binding
• Page 8.5 – 11 inches
• Bound at left side
• Use both side
• Accurately no.
3) Pagination
• page no of both copy should have same
4) Volume size and identification
• Not more than 2 inches thick
• Should have name of applicant, drug and
• NDA no.
5) Packing carton
• Box size 14(L) × 12(W) × 9.5(H) inches
Requirement
12

13
Basic requirements
Archival copy contains
❖ Application form (FDA 356th) : It contains,
• basic identification information
• as per form items no. 1 and 2 should bound together
• 3 to 12 submitted separately
• 13 and 14 separately
❖ Index -

14
Summary requirement
1) Labeling :
• Proposed label
• It is also called mini summary
2) Pharmacological class
• Intended use
• Potential clinical benefit
3) Foreign marketing history
• List of country who approved
same drug
• List of country who withdrawn
same drug
4) Chemistry, mfg., control
A) Drug substance
• Names:- name, synonym, code designation,
brand name, identification no. and chemical
name.
• Physical and chemical properties: MP, BP,
mol wt., solubility, mol. Formula structural
formula, PH, isomer, polymorphs.
• Stability
• Manufacture- Name and method.

15
B) Drug product
I. Composition
II. Dosage form
III. Manufacture
IV. Specification
V. Analytical method
VI. Container
VII. Closure
VIII.Stability
IX. Investigational formulation
7) Microbial summary
• Microbial spectra
• Mechanism of action
8) Clinical data summary and result
A) Clinical pharmacology
B) Overview of clinical studies
C) Controlled clinical studies
D) Uncontrolledclinical studies
E) Other studies and information
F) Safety summary
a) Extent of exposure
b) Adverse event
c) Clinical laboratorydata
e) Over dose
f) drug abuse
9) Discussion of benefit to risk relationship
and proposed post marketing studies.
10) Bioavailability summary
5) Nonclinical pharmacology and
toxicology summary
1. Pharmacological studies
2. Acute toxicity studies
3. Multidose toxicity studies
4. Mutagenicity studies
5. Reproduction studies
6. ADME studies
6) Human pharmacokinetic summary

16
NDA technical section requirement
1) Chemistry, manufacturing, and control
a) Drug substance
b) Product
2) Non clinical pharmacology and toxicology
3) Human pharmacokinetics
4) Bioavailability section
5) Microbiology
a) Mechanism of action
b) Pharmacokinetics
c) Antimicrobialactivity
d) Enzyme hydrolysis rate
e) Assessment of resistance
f) In vivo animal studies
g) In vitro studies during clinical trial
h) Published literature
i) Miscellaneous studies
6) Clinicaldata section
• adverse dose- response information
• drug -drug interaction
• drug disease interaction
Other NDArequirement
a) Safety updates
b) Sample : 4 samples
c) Method validation
d) Label : Draft labeling-4 copies
Final print labeling-12 copies
e) Case report

17
NDA and ANDA Requirements
Brand NameDrug
NDA Requirements
GenericDrug
ANDA Requirements
1. Chemistry 1. Chemistry
2. Manufacturing 2. Manufacturing
3. Controls 3. Controls
4. Labeling 4. Labeling
5. Testing 5. Testing
6. Animal Studies
7. Clinical Studies 6. Bioequivalence
8. Bioavailability

18
NDA Classifications
1. New MolecularEntity
2. New Salt of Previously Approved Drug (not a new molecularentity)
3. New Formulation of Previously Approved Drug (not a new salt OR a new molecularentity)
4. New Combination of Two or More Drugs
5. Already Marketed Drug Product- Duplication(i.e., new manufacturer)
6. New Indication (claim) for Already Marketed Drug (includesswitching marketing status
from prescription to OTC)
7. Already Marketed Drug Product- No Previously Approved NDA
Specification for FDAsDMFbinders
• Polyethylene binder:
➢Front- 248× 292 mm
➢Back- 248× 305 mm
➢Ink Colour must be BLACK
• Paper binder
➢Front 267×292mm
➢Back 267× 305mm
➢Ink must be BLACK , Marron Colour binder ink must be WHITE

19
FORM COLOUR DOCUMENT
FDA form 2226 Blue NDA archival binder
FDA form 2675 Red IND archival binder
FDA form 3316 Red Drug master file binder
FDA form 3316a Blue Drug master file binder
archival binder
FDA Form 2626a Red NDA chemistry binder
FDA Form 2626b Yellow NDA pharmacology binder
FDA Form 2626c Orange NDA pharmacokinetic binder
FDA Form 2626d White NDA microbiology binder
FDA Form 2626e Ten NDA clinical data binder
FDA Form 2626f Green NDA statistics binder
FDA Form 2626h Maroon NDA field submission chemistry
binder
FDA Form 2675a Green IND chemistry binder

20
Assembling applicationfor submission
Archival copy
▪ Reference copy for FDA ( i.e. retained by FDA ) .
▪ Locate information not containedin review copy.
▪ It must bound in bluecover
Review copy
▪ Divided in to five or six section containing technical
and scientific information separately bound.
▪ It contains copy of cover letter, application form,
overall summary,index,specific review section.
NDAContents
• The NDA have as many as 15 different section in addition to the Form FDA 356h itself.
• The specific content of NDA will depend on the nature of the drug product and the information
available at the time of submission the application.

21
NDA Content
Section 1
Section 2
Section 3
Section 4
Section 6
Section 5
Section 7
Section 12
Section 8
Section 11
Section 9
Section 10
Section 14
Section 13
Section 15
Index
Chemistry , manufacturing and
control
Summary
Human pharmacokinetics and
bioavailability
statistics
Clinical data
Safety update report
Sample and labeling
Case report tabulation
Nonclinical pharmacology and
toxicology
Clinical microbiology
Patent information
Case report form
Patent certification
other

NDA review
Usually six different teams responsible for reviewing NDA includes
1. Chemistry
2. Clinical
3. Pharmacology/ toxicology
4. Statistics
5. Biopharmaceutical
6. Microbiology
NDA (Ajay Lunagariya) 22

New Drug Development and Review Process
Steps from Test Tube to New Drug Application Review

Phases of clinical testing

NDA Review Process

FDA–Approval process
1.Fasttrack approval
Drug for
• Serious disease.
• Fill an unmet need.
• Must be requested by the
drug company .
• FDA 60 days review
decision.
2. Priority review
• A priority review designation is given to drug
that offer major advances in Treatment
• The goal for completing a priority review is 6
month
• It can given for drug used in serious/non serious
disease.
3. Acceleratedapproval
• In 1992 FDA instituted the accelerated approval regulation.
• Based on surrogate endpoint, not on clinical outcome.
• A surrogate endpoint is a marker- a laboratory measurement, or physical sign that is
used in clinical trial as an indirect or substitute measurement that represent a clinically
meaningful outcome, such as survival or symptom improvement.

Reference :
• Prescription New Drug Submission, RegulatoryAffairs Professional Society, 2000, 57-71
• Richard A. Guarino and Marcel Dekkar, New Drug Approval Process, 2nd edition,1987,39-319
• Howard C. Ansel , Pharmaceutical Dosage Forms and Drug Delivery System, 8th edition, 2006,44-
62.
• www.fda.gov/cder/regulatory/applications/ind_page_1.htm
• www.fda.gov/cder/ddms/ binders.htm
• Remington,”TheScience and Practice of Pharmacy”, 21st edition, Volume-1,965.
• www.fda.gov/cder/guidance/2125fnl.htm

NDA Approval Process.pdf

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