NDA Approval Process.pdf

New Drug Application Process for Drug Approval from FDA for Saling and Marketing of the Drug.

1. NDA
(NEW DRUG APPLICATION)
Presented By,
Ajay Lunagariya
ACP22PHCE002
M.PharmSem-1 (2022-23)
1

2. 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.
2NDA (Ajay Lunagariya)

3. 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
ofdisease 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
fordiagnosis, treatment, mitigation or prevention of any disease or disorder in human or animal which
exceptduring local clinical trial has not been used in the country to any significant extent and during local
clinical trialshas not been recognized in the country as effective and safe for the proposed claims.
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4. ❖Preclinical Testing
•Apharmaceuticalcompanyconductslaboratoryandanimalstudiestoshowbiologicalactivityofthe
compoundagainstthetargeteddisease,andthecompoundisevaluatedforsafety.Theseteststake
approximatelythreeandone-halfyears.
❖Investigational New Drug Application (IND)
•Aftercompletingpreclinicaltesting,thecompanyfilesanINDwithFDAtobegintotestthedrugin
people.TheINDbecomeseffectiveifFDAdoesnotdisapproveitwithin30days.
•TheINDshowsresultsofpreviousexperiments,how,whereandbywhomthenewstudieswillbe
conducted;thechemicalstructureofthecompound;howitisthoughttoworkinthebody;anytoxic
effectsfoundintheanimalstudies;andhowthecompoundismanufactured.
•Inaddition,theINDmustbereviewedandapprovedbytheInstitutionalReviewBoardwherethe
studieswillbeconducted,andprogressreportsonclinicaltrialsmustbesubmittedatleastannually
toFDA.
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5. ❖Clinical Trials, 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.
❖Clinical Trials, 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.
❖Clinical Trials, 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. 5NDA (Ajay Lunagariya)

6. ❖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. 6NDA (Ajay Lunagariya)

7. NEWDRUG 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?
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8. •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.
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9. 9NDA (Ajay Lunagariya)

10. OBJECTIVE OF NDA
❖Whetherthedrug'sproposedlabeling(packageinsert)isappropriate,andwhat
itshouldcontain.
❖Whetherthedrugissafeandeffectiveinitsproposeuse,andwhetherthebenefitsof
thedrugoutweightherisks.
❖Whetherthemethodsusedinmanufacturingthedrugandthecontrolsused
tomaintainthedrug'squalityareadequatetopreservethedrug'sidentity,
strength,quality,andpurity
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11. NDA FORM
❖Form FDA-356h. Application to market a new drug, biological or
an antibiotic drug forhuman use.
❖Form FDA 3397. User fee cover sheet.
❖Form FDA 3331. New drug application field report.
❖Impurity in drug substances.
❖Required specification for FDAs IND, and ANDA drug master file
binders.
❖Refusal to file.
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12. A) No of copies-
Before 1985-3 copies & now only2copies.
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) Assembling the 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
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13. 13NDA (Ajay Lunagariya)
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. 14NDA (Ajay Lunagariya)
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, codedesignation,
brand name, identification no. and​chemical
name.
•Physical and chemical properties:MP, BP,
mol wt., solubility, mol. Formulastructural
formula, PH, isomer, polymorphs.
•Stability
•Manufacture-Name and method.​

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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) Uncontrolled clinical studies
E) Other studies and information
F) Safety summary
a) Extent of exposure
b) Adverse event
c) Clinical laboratory data
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.Multi dose toxicity studies
4.Mutagenicity studies
5.Reproduction studies
6.ADME studies
6) Human pharmacokinetic summary

16. 16NDA (Ajay Lunagariya)
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) Antimicrobial activity
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) Clinical data section
•adverse dose-response information
•drug -drug interaction
•drug disease interaction
Other NDA requirement
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. 17NDA (Ajay Lunagariya)
NDA and ANDA Requirements
Brand Name Drug
NDA Requirements
Generic Drug
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. 18NDA (Ajay Lunagariya)
NDA Classifications
1.New Molecular Entity
2.New Salt of Previously Approved Drug (not a new molecular entity)
3.New Formulation of Previously Approved Drug (not a new salt OR a newmolecular entity)
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 (includes switchingmarketing status
fromprescription to OTC)
7.Already Marketed Drug Product -No Previously Approved NDA
Specification for FDAs DMF binders
• 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. 19NDA (Ajay Lunagariya)
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. 20NDA (Ajay Lunagariya)
Assembling application for submission
Archival copy
▪Reference copy for FDA ( i.e. retained by FDA ) .
▪Locate information not contained in review copy.
▪It must bound in blue cover
Review copy
▪Divided in to five or six section containing technical
and scientific information separatelybound.
▪It contains copy of cover letter, application form,
overall summary, index, specific reviewsection.
NDA Contents
•The NDA have as many as 15 different section in addition to the Form FDA 356hitself.
•The specific content of NDA will depend on the nature of the drug product andthe information
available at the time of submission the application.

21. 21NDA (Ajay Lunagariya)
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

22. NDA review
Usually six different teams responsible for reviewing NDA includes
1.Chemistry
2.Clinical
3.Pharmacology/ toxicology
4.Statistics
5.Biopharmaceutical
6.Microbiology
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New Drug Development and Review Process
Steps from Test Tube to New Drug Application Review

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Phases of clinical testing

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NDA Review Process

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FDA –Approval process
1.Fast track 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 givenfor drug used in serious/non serious
disease.
3. Accelerated approval
•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 signthat is
used in clinical trial as an indirect or substitute measurement thatrepresent a clinically
meaningful outcome, such as survival or symptomimprovement.

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Reference :
•Prescription New Drug Submission, Regulatory Affairs 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