This document discusses investigational new drug applications, the Orange Book, and 505(b)(2) applications. It provides an overview of the IND process including when an IND is needed, the content of an IND application, annual reporting requirements, and classifications of INDs. It also describes the Orange Book's listing of approved drugs and their therapeutic equivalence ratings. Finally, it gives a brief explanation of 505(b)(2) applications, including what products are allowed and examples of 505(b)(2) NDAs.

1. INVESTIGATIONAL NEW DRUG ,
ORANGE BOOK,
UNDERSTANDING ON 505(b) (2)
APPLICATIONS
Prepared By: S.Susena( M. Pharm Sem-2)
I.P.R . Department
Guided by: Y.Malyadri
S. S. J. Pharmacy College
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2. CONTENTS
INVESTIGATIONAL NEW DRUG (IND)
INTRODUCTION
PRE-IND MEETING
THE CONTENT AND FORMAT OF AN IND
APPLICATION
ORANGE BOOK
UNDERSTANDING ON 505(b) (2)
APPLICATIONS
CONCLUSION
REFERENCES
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3. 3
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 Federal Food, Drug, and Cosmetic Act requires
that all drugs have an approved marketing
application (NDA, BLA, ANDA) before they can be
shipped in interstate commerce.

5. 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.

6. 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

7. 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.
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8. Pre-IND Meeting
 A meeting between the sponsor and
the FDA frequently is useful in
resolving questions and issues raised
during the preparation for an IND.
 The FDA encourages such meetings
to the extent that
1.They aid in the solution of
scientific problems and
2. To the extent that the FDA has
available resources. 8

9. The Content and Format of an IND
Application
The content and format of an initial IND is laid out
in 21 CFR Part 312
Cover Sheet —312.23(a)(1)FDA Form 1571
Table of Contents —313.23(a)(2)
Introductory Statement and General
Investigational Plan —312.23(a)(3)
Investigator’s Brochure —312.23(a)(5)
Clinical Protocol —312.23(a)(6)
Chemistry Manufacturing and Controls
Information —312.23(a)(7) 9

10. Pharmacology and Toxicology Information —
312.23(a)(8)
Previous Human Experience —312.23 (a)(9)
Additional Information —312.23(a)(10)
Relevant Information —312.23(a)(11)
Other Important Information about the Format,
Content and Submission of an IND
The FDA Review of the IND
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11. IND review flow chart
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12. Additional Information —312.23(a)(10) :
This section is used to present information on special
topics.
Drug dependence and abuse potential.
Radioactive drugs.
Pediatric studies. Any plans the sponsor has for assessing
the safety and effectiveness of the drug in the pediatric
population.
Other information. Any other relevant information that
might aid in the evaluation of the proposed clinical
investigations.
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13. Relevant Information —312.23(a)(11) :
Any information specifically requested by
the FDA that is needed to review the IND
application.
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14. Other Important Information about the
Format, Content and Submission of an IND :
For clinical studies that will be submitted as part of an NDA
or BLA, IND sponsors must collect financial disclosure
information from each investigator or sub investigator who
is directly involved in the treatment or evaluation of clinical
trial subjects.
The sponsor may also reference a drug master file (DMF) in
the IND application that contains important information
necessary to complete review of the IND.
Reports or journal articles in a foreign language must be
accompanied by a complete and accurate English
translation. Each IND submission must include a four-digit
serial number.
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15. IND Annual Reports :
The IND regulations require IND sponsors to submit an
annual report that provides the FDA with a brief update on
the progress of all investigations included in the IND.
The annual report must contain the following information:
Individual study information ,Summary Information ,The
general investigational plan for the coming year.
If the investigator brochure was modified during the year, a
list of the changes along with a copy of the new brochure
A listing of any significant foreign marketing developments
with the drug, e.g., approval in another country or
withdrawal or suspension of marketing approval.
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16. CLASSIFICATION of INDs
INDs can be classified on four dimensions:
Commercial / Noncommercial,
Standard / Emergency,
Paper / Electronic,
Original / 505(b)(2).
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17. Orange book
Its official title is Approved Drug Products with
Therapeutic Equivalence Evaluations .
Commonly known as the Orange Book due to the
orange cover of the original print version, it is the Food
and Drug Administration's list of all drugs approved in
the United States as safe and effective.
In addition to listing all approved drugs, the Orange
Book is also the authoritative source of information on
the therapeutic equivalence of drug products.
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18. THE GREEN BOOK:
the Green Book had some additional and advantageous
features. For example, it listed drugs for which “authorized
generics” were available, information which the Orange book
does not contain
THE BLUE BOOK:
The FDA publication Requirement of Laws and Regulations
Enforced by the U.S. Food and Drug Administration. It has
been discontinued as of October 2002. In its place there is a
Wealth Of Compliance Information on the FDA
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19. The Orange Book consists of five main
sections:
an introduction, a “how to use” section,
the drug product lists,
appendices, and
a patent
exclusivity information addendum.
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20. TE Codes
TE codes are divided into two categories, A and B
‘A’ Drugs are those which the FDA considers to be
therapeutically equivalent and, therefore, substitutable
where permitted by the prescriber. They are further
divided as follows:
‘B’ Drugs are those which the FDA considers NOT to be
therapeutically equivalent due to actual or potential
bioequivalence problems which have not been resolved. B-
rated drugs are not legally substitutable
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21. CODE A product that FDA considers
AA: Products in conventional dosage form.
AB, AB1, AB2, AB3: Products meeting necessary bio-
equivalence requirements
AN: Solutions and powder for aerosolization
AO: Injectable oil solutions
AP: Injectable aqueous solutions and intra-venous non-
aqueous solutions
AT: Topical products
AB: actual or potential bioequivalence problems have
been resolved through adequate in vivo and/or in vitro
testing. 21

22. BC Extended-release dosage forms (capsules, injectables and
tablets)
BD Active ingredients and dosage forms with documented
bioequivalence problems
BE Delayed-release oral dosage forms
BN Products in aerosol-nebulizer drug delivery systems
BP Active ingredients and dosage forms with potential
bioequivalence problems
BR Suppositories or enemas that deliver drugs for systemic
absorption
BS Products having drug standard deficiencies
BT Topical products with bioequivalence issues
BX Drug products for which the data are insufficient to determine
therapeutic equivalence
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23. UNDERSTANDING ON 505(b) (2)
APPLICATIONS
The 505(b)(2) New Drug Application – A
Rapid Approval Route
The 505(b)(2) application is one of three
established types of new drug application
(NDA), and it is a pathway to approval that
can potentially save pharmaceutical
sponsors both time and money
23

24. Basics of the 505(b)(2)
Considered a full NDA
Must be the same active product (API)
Reporting requirements
 Previously reported safety and efficacy
 Information from studies not conducted by applicant
 Relying on FDA’s prior conclusions on safety and/or
efficacy from
 Non-clinical or Clinical
 Information where applicant lacks the right of reference
New studies to support change
24

25. NDA 505(b)(2)
Products allowed under 505(b)(2):
Changes to previously approved drugs
Dosage regimen
API change (salt, ester, complex, chelate,)
New indication
Rx/OTC switch
Bioinequivalent to, but not inferior bioavailability
compared to the Reference Listed Drug (RLD)
Formulation changes outside 505(j) limits
Can not be used for products eligible for ANDA

26. NDA 505(b)(2)
Products not allowed under 505(b)(2):
• That are covered under Section 505(j)
• For which the only difference is lower
extent of absorption than reference drug
• For which the only difference is an
unintended lower rate of absorption than
reference drug
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27. 505(b)(2) NDA Examples
Route of Administration
IV to other parenteral routes
Active Ingredient
Change in salt, racemate or enantiomer
New Molecular Entity
Prodrug of an approved drug
Active metabolite of an approved drug
New combination product
Combining actives previously approved individually
Formulation change
Excipient not allowed under 505(j)
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28. The 505(b)(2) Process
Major Elements
Meetings and Materials
Pre-IND
EOP2
Pre-NDA (pre-BLA)
Submissions
IND
NDA
FDA Interactions 28

29. CONCLUSION
The IND application allows a company to initiate and
conduct clinical studies of their new drug product.
The Orange Book is also the authoritative source of
information on the therapeutic equivalence of drug
products.
The 505(b)(2) pathway is potentially low risk and has
advantages in regards to time and money
and,perhaps,exclusivity. Can get early FDA feedback
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30. References
www.fda.gov/opacom/laws/lawtoc.htm
www.fda.gov/cder/guidance/index.htm
www.fda.gov/cber/guidelines.htm
www.fda.gov/cder/handbook/
www.fda.gov/cder/mapp.htm
www.fda.gov/oc/gcp/default.htm
www.regsource.com/default.html
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