new drug application [nda]

05/01/2023 Sagar Kishor Savale 1

New Drug Application[NDA]

Mr. Sagar Kishor Savale[Department of Pharmaceutics]

[email protected]

Department of Pharmacy (Pharmaceutics) | Sagar Savale

mailto:[email protected]


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.


DefinitionsDrug: 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.

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.


Drug

All medicines for internal or external use of human beings or animals or

All substances intended to be used for or in the diagnosis, treatment mitigation or prevention of any disease or disorder in human and animal.

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

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.


New Drug Application (NDA)

An application submitted by the manufacturer of a drug to the FDA - after clinical trials have been completed - for a license to market the drug for a specified.

New Drug Application (NDA) is the vehicle in the United States through which drug sponsors formally propose that the FDA approve a new.

Abbreviated New Drug Application (ANDA)

An application for a license to market a generic (or a duplicate) version of a drug that has already been granted an approval under a full NDA (i.e. the drug has already met the statutory standards for safety and effectiveness.


OBJECTIVE OF NDAWhether 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.


NDA FORMForm FDA-356h. Application to market a new drug, biological or an antibiotic drug for

human 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.


FORM NO 356TH


Approval time TOTAL APPROVAL YEAR NO

AVG APPROVAL TIME (MONTHS)

DECEMBER APPROVAL

1980 12 35 2

1981 27 31 7

1982 28 29 6

1983 14 29 2

1984 22 39 8

1985 30 32 16

1986 20 34 10

1987 21 32 15

1988 20 31 13

1989 23 33 10

1990 23 27.7 -


Introduction of NDA and ANDA NDA and ANDA is application is send to FDA for approval of new drug and abbreviated

( generic) new drug.

When new drug application is submitted to food and drug administration it must be carefully prepared , comprehensive , readable and well indexed.

The guideline issued by FDA has to follow Should follow D & C Act.

Code of federal regulation title 21 section 314 ( 21 CFR 314) is provided a brief description for NDA and ANDA

Experience : It is generally planned 3 years ago.


Requirement Requirement for NDA Format requirement A) No of copies - Before 1985- 3 copies & now only 2 copies. Archival copy Review copy 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 -12- 9.5 inches


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 -


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.


B) Drug product

a) Composition

b) Dosage form

c) Manufacture

d) Specification

e) Analytical method

f) Container

g) Closure

h) Stability

i) Investigational formulation


5) Nonclinical pharmacology and toxicology summary A) Pharmacological studies B) Acute toxicity studies C) Multi dose toxicity studies D) Mutagenicity studies E) Reproduction studies F) ADME studies 6) Human pharmacokinetic summary

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 informationF) Safety summary

a) Extent of exposure b) Adverse event c) Clinical laboratory data e) Over dose f) drug abuse


Guidance Documents for NDA

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 product.


9) Discussion of benefit to risk relationship and proposed post marketing studies. 10) Bioavailability summary

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


NDA and ANDA Requirements

Brand Name Drug Generic DrugNDA Requirements ANDA Requirements

1. Chemistry 1. Chemistry2. Manufacturing 2. Manufacturing3. Controls 3. Controls4. Labeling 4. Labeling5. Testing 5. Testing6. Animal Studies7. Clinical Studies 6. Bioequivalence8. Bioavailability


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 new molecular 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 switching marketing status from prescription 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


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


FORM COLOUR DOCUMENT

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 Tan NDA clinical data binder

FDA Form 2626f Green NDA statistics binder

FDA Form 2626h Marron NDA field submission chemistry binder

FDA Form 2675a Green IND chemistry binder


Assembling application for submission

FDA

Archival copy Review copy


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 separately bound.

It contains copy of cover letter, application form, overall summary, index, specific review section.


NDA Contents

• 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.

05/01/2023 Sagar Kishor Savale

NDA content

35

section 1

Section 2

Section 3

Section 4

Chemistry , manufacturing and control

Section 5 Nonclinical pharmacology and toxicology

Index

summary

Sample and labeling


NDA Contents

36

Section 6

Section 7

Section 8

Section 9

Section 10

Human pharmacokinetics and bioavailability

Clinical microbiology

Clinical data

Safety update report

statistics


NDA Contents

37

Section 11

Section 13

Section 12

Section 14

Case report tabulation

Case report form

Patent information

Patent certification

Section 15 other


THE TWO TRANSLATIONAL BLOCKS

Basic Biomedical

Research

Clinical Science

and Knowledge

Goal: Improved

HealthBlock 1 Block 2

Translation from basic science to human studies

Translation ofnew knowledge

into clinical practice


DRUG DEVELOPMENT PROCESS


NDA review

Usually six different teams responsible for reviewing NDA includes1. Chemistry 2. Clinical3. Pharmacology/ toxicology4. Statistics5. Biopharmaceutical6. Microbiology


New Drug Development and Review Process

Steps from Test Tube to New Drug Application Review

41


Phases of clinical testing

Phase Number of patients

Length Purpose Percent successfully completing

Phase 1 20-100 Several months Mainly safety

67Phase 2 Up to several

hundredSeveral months

to two yearsSome short-

term safety but mainly

effectiveness

45

Phase 3 Several hundred to several thousand

1-4 years Safety, effectiveness,

dosage5-10


NDA Review Process

44


FDA –Approval process


Fast track approval

Drug for

Serious disease.

Fill an unmet need.

Must be requested by the drug company .

FDA 60 days review decision.


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 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.


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.


Common Technical Documents

MODULE-1: Administrative Information

MODULE- 2: Quality Overall Summary

MODULE-3: Quality

MODULE-4: Non- Clinical Studies

MODULE-5: Clinical Studies


MODULE 1

MODULE 3 MODULE 4 MODULE 5

MO

DU

LE

2

Regional Admin.

Information

Quality

Overall

summary

Non Clinical overvie

wNon Clinical Summary

Clinical

Overview

Clinical Summary

Quality Non Clinical Report

Clinical Report

Not

part of

CTD

CTD

The CTD Triangle

50


The NDA in CTD FormatModule 1 is not part of the CTD because it is not harmonized

CTD NDA: 314.50Module 1 a) Application form

c)2.1 Annotated text of proposed labeling

e)Samples and Labelingh)Patent informationi) Patent certificationj)Claimed exclusivity

Module 2 c)Summariesd)5.7 Abuse potential

Module 3 d)1 CMC

Module 4 d)2 Nonclinical pharm/tox

Module d)3 Human PKd)4 Microbiologyd)5 Clinical data d)6 Statistical sectionf) CRF and CRT

52


Difference between NDA & ANDA

NDA ANDAApplicable for new drug Applicable for generic drug

Money requirement is high Less money compare to NDA

12 to 15 year required 1 to 2 year required

Cost of drug is high Cost of drug is less

Non clinical and clinical study are essential. Bioavailability and bioequivalence study essential


REFERENCEwww.hhs.govwww.fda.comwww.usfda.comwww.slideshere.comwww.mpssociety.orgwww.jpsr.pharmainfo.in Richard A. Guarino , (1993) New drug Approval process, Marcel Dekker, 2nd edition, p.no

256-319 Ram .I. Mahato pharmaceutical dosage form and drug delivery CRC press pharmacy edu.

series p.no 7

http://www.hhs.gov/

http://www.fda.com/

http://www.usfda.com/

http://www.slideshere.com/

http://www.mpssociety.org/

http://www.jpsr.pharmainfo.in/

new drug application [nda]

Health & Medicine