Introduction to Investigational new drug application, New drug application, Abbrevated new drug application

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PRESENTATION ON
INTRODUCTION TO INDA/NDA/ANDA
PRESENTED By
MR. ROHIT D. BHOSALE
(M. PHARM)
Department of Pharmaceutics
G.I.P.E.R LIMB SATARA
SHIVAJI UNIVERSITY, KOLHAPUR
2014

2. 2
1] IND
Introduction
Types of IND
Guidance documents of INDs
Format and Content of INDs
IND review flow chart
FDA requirements for generic drugs
Hatch-Waxman Act
Orange book
USFDA approval process
Conclusion

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New Drug Development Process.
Initial
Synthesis
Animal
Testing
I
N
D
A
P
P
L
I
C
A
T
I
O
N
PhaseI
PhaseII
PhaseIII
PhaseIV
Adverse
Reaction
Reporting
Surveys/
Sampling
Testing
Inspections
Range 1-3Yrs.
Avg:18 Mos.
FDATime
30 Day
Safety Review
Range 2-10Yrs.
Avg :5Yrs.
NDA
Submitted
NDA
Approved
Range 2 Mon –
7Yrs.Avg:24 Mos.
Average of Approximately 100 Months From Initial Synthesis to Approval of NDA
Treatment Use
Preclinical Clinical Development NDA Review Post-Marketing

4. INTRODUCTION
 An Investigational New Drug Application (IND) is a submission to the Food and Drug
Administration requesting permission to initiate a clinical study of a new drug product.
 The IND application allows a company to initiate and conduct clinical studies of their new
drug product.
 The IND application provides the FDA with the data necessary to decide whether the new
drug and the proposed clinical trial pose a reasonable risk to the human subjects
participating in the study.

5. WHEN DO I NEED AN IND?
 An IND is required any time you want to conduct a clinical trial of an unapproved
drug.
 The Act further defines a new drug, in part, as “any drug the composition of which is
such that such drug is not generally recognized as safe and effective for use under the
conditions prescribed, recommended, or suggested in the labeling.

6. WHEN YOU DON’T NEED AN IND?
 An IND is not required to conduct a study if the drug:
 Is not intended for human subjects, but is intended for in vivo testing or
laboratory research animals (non clinical studies)
 Is an approved drug and the study is within its approved indication for use.
6

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Types of INDs:
1) Investigator INDs: submitted by a physician who both initiates and conducts an
investigation, and under whose immediate direction the investigational drug is
administered or dispensed.
2) Commercial INDs: They are applications that are submitted primarily by
companies whose ultimate goal is to obtain marketing approval for a new product.
3) Emergency Use IND: This IND allows the FDA to authorize use of an
experimental drug in an emergency situation.
4) Treatment IND: this IND may be submitted for experimental drugs showing
promise in clinical testing of serious or immediately life-threatening conditions.

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The IND application must contain information in three broad
areas:
1) Animal Pharmacology and Toxicology Studies - Preclinical data to permit an
assessment as to whether the product is reasonably safe for initial testing in humans.
2) Manufacturing Information –
Includes composition, manufacturer, stability, and controls used for manufacturing the drug
substance and the drug product.
3) Clinical Protocols and Investigator Information - Detailed protocols and clinical studies to
assess whether the initial-phase trials will expose subjects to unnecessary risks.
Investigators information contains administration of experimental compound to assess
whether they qualified clinical trials.

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Resources for IND Applications
Pre-IND Consultation Program:
CDER offers a Pre-Investigational New Drug Application (IND) Consultation Program to
foster early communications between sponsors and new drug review divisions in order to
provide guidance on the data necessary to warrant IND submission.

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Guidance Documents for INDs:
1. Guidance for Industry: CGMP's for Phase 1 Investigational Drugs
2. Guidance for Industry: Exploratory IND Studies
3. Content and Format of Investigational New Drug Applications (INDs) for Phase 1
Studies of Drugs Including Well Characterized, Therapeutic, Biotechnology-
Derived Products.
4. Q & A - Content and Format of INDs for Phase 1 Studies of Drugs, Including
Well-Characterized, Therapeutic, Biotechnology-Derived Products. This guidance
is intended to clarify when sponsors should submit final, quality-assured
toxicology reports and/or update the Agency on any changes in findings since
submission of non-quality-assured reports or reports based on non-quality-assured
data.

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5.Bioavailability and Bioequivalence Studies for Orally Administered Drug
Products -
6.IND Exemptions for Studies of Lawfully Marketed Drug or Biological Products
for the Treatment of Cancer.
7.Drug Master Files: A Drug Master File (DMF) is a submission to the Food and
Drug Administration (FDA) that may be used to provide confidential detailed
information about facilities, processes, or articles used in the manufacturing,
processing, packaging, and storing of one or more human drugs.

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FORMAT AND CONTENT OF IND-
A. Cover sheet (Form FDA-1571)
a. Name, address, telephone of sponsor
b. Identification of phases
c. Commitment not to begin CT until IND approval
d. Commitment by IRB- Form 56
e. Commitment for conducting CT- accordance with regulations
f. Name, title – Monitor
g. Name, title – person(s) for reviewing
h. Name, Address of CRO, if any
i. Signature of sponsor
B. Table of contents
C. Investigators brochure
D. Study protocol
E. Investigator facilities & IRB data
F. Chemistry manufacturing & control data
G. Previous human experience

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IND review flow chart

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Two important outcomes from the IND discussion:
30 days after an IND is submitted to the FDA, if the sponsor has
not heard anything from the FDA it can be assumed that the drug is
not on a clinical hold and clinical trials may be started
The Investigator‟s Brochure, which will be used during that
important first clinical study and in every clinical study thereafter,
acts as the approved labeling for the drug while it is under an IND.

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NDA (NEW DRUG APPLICATION) FILING

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NDA (New Drug Application
 The vehicle through which drug sponsors formally propose that
the regulatory body approve a new pharmaceutical for sale and
marketing.
 Form 44
 The data gathered during the animal studies and human clinical
trials of an Investigational new product become part of the NDA.

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GOAL OF NDA
Provide enough information to permit FDA reviewers to establish the
following:
 Safety & effectiveness of drug?
 Benefits overweigh risks?
 Is the drug’s proposed labelling (package insert) appropriate, and
what should it contain?
 Are the methods used in manufacturing (Good Manufacturing
Practice, GMP) the drug and the controls used to maintain the drug’s
quality adequate to preserve the drug’s identity, strength, quality,
and purity?
Risk Benefit

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Guidance documents to help prepare NDAs include:
1. Bioavailability and Bioequivalence Studies for Orally Administered Drug Products -
2. Container Closure Systems for Packaging Human Drugs and Biologics.
3. Format and Content of the Chemistry, Manufacturing and Controls Section of an
Application.
4. Format and Content of the Microbiology Section of an Application.
5. Format and Content of the Clinical and Statistical Sections of an Application.
6. Format and Content of the Summary for New Drug and Antibiotic Applications.
7. Formatting, Assembling and Submitting New Drug and Antibiotic Applications.

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8. Supporting Documentation in Drug Applications for the Manufacture of Drug
Substances.
9. Documentation for the Stability of Human Drugs and Biologics.
10.Samples and Analytical Data for Methods Validation.
11.Supporting Documentation in Drug Applications for the Manufacture of Drug
Products.
12.NDAs: Impurities in Drug Substances.
13.Format and Content of the Human Pharmacokinetics and Bioavailability Section of
an Application.
14.Format and Content of the Nonclinical Pharmacology/Toxicology Section of an
Application.
Guidance documents to help prepare NDAs include:

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15. Clinical Evidence of Effectiveness for Human Drug and Biological Products:
Describes the quantity of evidence, and the documentation of the quality of
evidence necessary to support a claim of drug effectiveness.
16. Drug Master Files.

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Fundamentals of NDA Submission :
1) Index
2) Summary
3) Chemistry, Manufacturing, and Control;
4) Samples, Method Validation Package, and Labeling
5) Nonclinical Pharmacology and Toxicology
6) Human Pharmacokinetics and Bioavailability
7) Microbiology (for anti-microbial drugs only);
8) Clinical Data;
9) Safety Update Report.
10) Statistical;
11) Case Report Tabulations;
12) Case Report Forms;
13) Patent Information;
14) Patent Certification; and
15) Other Information.

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Classification of drugs in NDA
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.

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GENERAL REQUIREMENTS for filing an NDA
The new (present) NDA regulations require that an application be submitted in two copies :
(A) review copy.
 SUMMARY
 THE SAFETY UPDATE REPORTS
(B) archival copy.
 CHEMISTRY, MANUFACTURING AND CONTROLS.
 NONCLINICAL PHARMACOLOGY
ANDTOXICOLOGYHUMAN PHARMACOKINETICS
AND BIOAVAILIBILITY MICROBIOLOGY
 CLINICAL DATA
 STATISTICS
 LABELING
 Patent Information

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NDA REGULATIONS
Review Time Frames (21 CFR 314.100):
 Within 180 days of receipt of an application, the FDA will review and issue an approval,
approvable, or not approvable letter. This 180-day period is called the review-clock” During
the review period an applicant may withdraw an application (21 CFR 314-65) and later
resubmit it.
Filing Time Frames (21 CFR 314.101):
 Within 60 days after the FDA receives an application, a determination will be made whether
the application may be filed.
 If FDA files the application, the applicant will be notified in written. The date of filing will be
the date 60 days after the FDA received the application.
 The date of filing begins the 180-days period of the review. If FDA refuses to file the
application, the sponsor will be given the opportunity to meet with FDA to discuss the reasons
why the application is not file able.

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NDA review flow chart

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An Abbreviated New Drug Application (ANDA) contains data submitted to FDA's
Center for Drug Evaluation and Research, Office of Generic Drugs, for review and
ultimate approval of a generic drug product.
 Once ANDA is approved, an applicant may manufacture and market the generic drug
product to provide a safe, effective, low cost alternative to the public.
A generic drug product is the one that is comparable to an innovator drug product in
dosage form, strength, route of administration, quality, performance characteristics
and intended use. All approved products, both innovator and generic, are listed in
FDA's Approved Drug Products with Therapeutic Equivalence Evaluations (Orange
Book).
(ANDA) Introduction

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Generic drug applications are termed "abbreviated" because they are generally not
required to include preclinical (animal) and clinical (human) data to establish safety
and effectiveness. Instead, generic applicants must scientifically demonstrate that their
product is bioequivalent (i.e., performs in the same manner as the innovator drug).
Use of bioequivalence as the base for approving generic drug products was
established by the "Drug Price Competition and Patent Term Restoration Act of
1984," also known as the WAXMAN-HATCH ACT.

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Guidance Documents for ANDAs
Guidance documents to help prepare ANDAs are listed together in the following categories:
1. Generics :
 Generics (Draft - Distributed for comment purposes only).
 Procedural Draft: Applications Covered by Section 505(b)(2). This provision permits FDA to
rely, for approval of an NDA, on data not developed by the applicant.
2. Biopharmaceutics:
 Bioavailability and Bioequivalence Studies for Orally Administered Drug Products -
3. Drug Master Files.
4.Guidance for Industry: Changes to an Approved NDA or ANDA
5.Refusal to Receive: Clarifies CDER's decisions to refuse to receive an incomplete application.
6.Inactive Ingredient Database: This database contains all inactive ingredients present in
approved drug products or conditionally approved drug products currently marketed for human
use.

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MANUFACTURING AND CONTROL REQUIREMENTS OF THE ANDA:
 FDA Manufacturing and Controls guidelines:-
1.Guideline for the format and content of an application summary.
2.Guideline for the format and content of the chemistry, manufacturing, and controls
section of an application.
3.Guideline for stability studies for Human drugs and Biologics
4.Guideline for packaging of Human Drugs and Biologics.
5.Guideline for submitting supporting documentations in drug applications for the
manufacture of drug substances.
6. Guideline for submitting supporting documentation for the manufacture of finished
dosage forms.

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7. Guidelines for drug master files. –
 Requirements for Drug substances sources:
 Specifications for drug substances:
 Drug product requirements:

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180-Day Generic Drug Exclusivity under the Hatch-Waxman Amendments to the
Federal Food, Drug, and Cosmetic Act
WAXMAN HATCH AMENMENTS BENIFITS
TO INOVATOR’S COMPANIES TO GENERIC DRUG COMPANIES
IF SUIT
180 DAY EXCLUSIVITY PERIOD
TO CHALLEGE PATENT DRUG
45 DAY TO CLAIM
DELAYED FOR 30 MONTHS
NOT SUIT

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ANDA CERTIFICATION
CLAUSES
PARAGR
APH I
PARAGR
APH II
PARAGR
APH III
PARAGR
APH IV

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PARA-I
Required patent
information has
not been filed.
FDA may approve
generics
immediately, one
or more applicants
may enter.
PARA-II
Patent has expired
FDA may approve
generics
immediately, one
or more applicants
may enter.

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PARA-III
Patent not expired,
will be expired on a
specific date.
FDA may approved
ANDA effective on
the date of
expiration, one or
more applicant may
enter.
PARA-IV
Patent is invalid or
non infringed by
generic applicant.
Generic applicant file
notice to patent
holder.

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PARA IV
CERTTIFICATION
After 45 days Patent
Holder doesn’t sue
applicant ► FDA may
approve ANDA.
ANDA Applicant
granted
approval.
After 45 days Patent
Holder sues the
Applicant ►
30months stay
granted to Patent
Holder.
30 Months stay
expired
For the first
Applicant the
EMR of 180 days
starts with
court’s decision.
Subsequent
approvals for EMRs
are granted after
expiry of first
applicant’s 180 days.
30 Months stay
not expired.

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30 Months stay not
expired
If judgement’s in
favour of Patent
Holder ► FDA can
not approve ANDA
untill patent expiry.
No entry occurs
untill Patent Expiry.
Judgement favouring
ANDA ► EMR of 180
days begins for first
applicant.
First Applicant
enters, subsequent
applicants enter only
after expiry of EMR
for the First
Applicant.

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ANDA review flow chart

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CONCLUSION
1.IND
 The data obtained during animal studies and human clinical trials of IND becomes part of
NDA.
 30 days after an IND is submitted to the FDA, if the sponsor has not heard anything from the
FDA it can be assumed that the drug is not on a clinical hold and clinical trials may be started.
2.NDA
 The date of filing begins the 180-days period of the review. If FDA refuses to file the
application, the sponsor will be given the opportunity to meet with FDA to discuss the
reasons why the application is not file able.

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ANDA

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REFERENCES:
1. www.fda.gov
2. www.drugs.com/new-drug-applications.html
3. gateway.nlm.nih.gov
4. en.wikipedia.org/wiki/New_Drug_Application
5. www.news-medical.net
6. www.genengnews.com
7. oig.hhs.gov/oei/reports/oei-01-01-00590.pdf
8. en.wikipedia.org/wiki/Investigational_New_Drug
9. www.mdci.com
10. www.accessdata.fda.gov

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11. www1.pointcross.com
12. www.domain-b.com
13. www.researchgate.net
15. pharmtech.findpharma.com
16. www.ftc.gov/be/v990016.shtm
17. www.activery.com/
18. www.access.gpo.gov