Investigational New Drug Application and New Drug Application

1. IND: INVESTIGATIONAL NEW DRUG APPLICATION
BHAGYASHREE PARANDE

3. WHAT IS AN IND?
• An IND is an application submitted to the FDA seeking
permission to use an unapproved drug (or biologic) in
a clinical investigation.
When is an ind required?
• An ind is always required prior to initiation of a clinical
study of an investigational new drug in the u.S. In
addition an IND is required before initiation of a
clinical study of the drug approved for some uses.

4. WHAT IS THE LEGAL BASIS FOR AN IND?
• T
• The requirement for an investigational new drug application is
defined in the law governing the development of new drugs in the
U.S. I.E. The federal food, drug and cosmetic act (FD & C act)
• The fundamental requirements of the FD & c act for new drugs are
as follows:
1. Proof of safety
2. Substantial evidence of efficacy
3. Informative labeling for the product
4. Demonstration of manufacturing of the product to the desired
strength, quality, purity and identity.
5. Signed agreement from investigators

5. ESSENTIAL PRINCIPLE OF AN IND
• IND must present adequate information to permit the FDA to
evaluate the drug’s suitability for use in the proposed clinical
study.
• The central focus of the initial ind should be the general
investigational plan and the protocol for the first proposed human
study.
• To assure that human subjects who participate in the proposed
study will not be exposed to unreasonable and significant risk.

6. CONTENT OF AN INITIAL IND
• Form FDA 1572
• Table of contents
• Introductory statement
• General investigational plan
• Investigators brochure
• Clinical protocols
• Chemistry, manufacturing and control data
• Pharmacology and toxicology data
• Previous human experience

7. INTRODUCTORY STATEMENT
• Description of the investigational drug
• All active ingredients
• Drug’s pharmacological classification
• Structural formula
• Route of administration
• Summary of previous human experience.
• Formulation of the dosage forms.
• Objectives and planned duration of proposed clinical
investigation

8. INVESTIGATIONAL PLAN
• Description of clinical studies planned for the
experimental drug
• Purpose for the drug or research study
• Indications to be studied
• Types of trials to be initiated
• Number of study subjects
• Risks

9. INVESTIGATOR’S BROCHURE 21 CFR 312.23(5)(I)-
(V)
• Structural formula of drug
• Summary of pharmacological, toxicological, and
pharmacokinetic effects in animals
• Safety and effectiveness
• Reprints of related articles
• Purpose of study
• Dose/dose frequency
• Method of administration
• Monitoring procedures

10. CLINICAL PROTOCOLS
• FDA reviews protocols to
• Ensure subjects not exposed to any unnecessary risks
• Phase 2 and 3 studies designs are adequate to
provide the type and amount of information
• Demonstrate effectiveness and safety
• Considered the most important part of the IND
• Ind review of protocols is intended to evaluate safety of
the drug
• Estimate number of subjects
• Describe safety
• Exclusion and inclusion
• Describe dosing regimen

11. CHEMISTRY, MANUFACTURING AND
CONTROL DATA (CMC)
• Determine the adequacy of methods used to
manufacture and assay investigational
compounds
• Safety concerns
• Describe drug substance
• Method of preparation
• Reagent and solvents
• Acceptable limits and analytical methods to
ensure quality and purity of drug

12. PHARMACOLOGY AND
TOXICOLOGY DATA
• PHARMACOLOGY AND DRUG DISPOSITION
• INTEGRATED TOXICOLOGY SUMMARY

13. CATEGORIES OF IND
1. Commercial inds - goal is to obtained marketing
approval for a new product.
2. Non-commercial inds – these include
A) investigator IND- in this case, the physician is both
the sponsor and investigator.
B) emergency use ind- fda authorize immediate
dispensing of a non-approved drug in a life-
threatening situation when no standard acceptable
therapy is available.
C) treatment ind- fda will permit investigational drug to
be used to treat a serious or life threatening disease,
or if there is no comparable alternative drug
available.
Ex-advanced cases of aids, herpes simplex
encephalitis and subarachnoid hemorrhage.

14. SUBMISSION OF THE IND
• Sponsor must submit
• Original
• Two copies
• Translation required
• Accurate and completed english translation for
any information written in a foreign language
• Must submit original foreign language document
on which translation was based

15. THIRTY DAYS FOR INTIAL INDS
:
• THE FDA MUST HAVE TIME TO REVIEW AN INITIAL
IND BEFORE THE INVESTIGATION AND THE FIRST
CLINICAL INVESTIGATION IS INITIATED.
• THIS REVIEW TIME IS ESSENTIAL TO PROTECT THE
PUBLIC HEALTH BECAUSE THE FDA MUST ASSURE
THAT. BASED ON THE EVIDENCE OF PRESENTED IN
THE INITIAL IND, IT IS REASONABLE FOR PROCEED
WITH THE FIRST PROPOSED CLINICAL INVESTIGATION.

16. FDA REVIEW OF INITIAL INDS:
• INITIAL INDS FOR INVESTIGATIONAL DRUGS ARE SENT BY THE SPONSOR TO THE
APPROPRIATE REVIEWER DIVISION OF THE FDA’S CENTER FOR DRUG
EVALUATION AND RESEARCH (CDER).
• INDS ARE ASSIGNED BY THERAPEUTIC CATEGORY TO THE RELEVANT FDA
REVIEWING DIVISION.
• A REVIEW TEAM IS ASSEMBLED TO WORK IN MULTIDISCIPLINARY
COLLABORATIVE EFFORT TO REVIEW THE IND .
• THE REVIEW TEAM CONSISTS OF REGULATORY REVIEWER FROM
• EACH OF TECHNICAL DISCIPLINES PLUS REVIEW COORDINATOR.

17. Medical officer
Consumer
safety
officer
Clinical
Pharmacologist
Chemist
Biostatitian
Pharmacologis
t
Microbiologis
t
Member of the FDA’s review team for a drug regulatory application

18. NATURE OF FDA REVIEW OF THE INITIAL IND :
• The IND contain sufficient information to allow reviewer to
assess risk to human who will enter the proposed study.
• Humans will not be exposed to unreasonable or significant risk
or illness or injury from the drug.
• The proposed clinical investigator is qualified with training and
experience to conduct the proposed study.
• The clinical investigator’s brochure in not misleading,
erroneous or materially incomplete.

19. TO DELAY/SUSPEND A STUDY
• PHASE I CLINICAL HOLDS
• SUBJECT SAFETY CONCERNS
• PHASE II & III CLINICAL HOLDS
• CONCERNS ABOUT SAFETY OR EFFICACY

20. IND REVIEW FLOW CHART

21. NDA CLASSIFICATIONS
CDER classifies new drug applications with a code that reflects
Both the type of drug being submitted and its intended uses.
• New molecular entity
• New salt of previously approved drug
• New formulation of previously approved drug
• New combination of two or more drugs
• Already marketed drug product – duplication by new manufacturer
• New indication for already marketed drug ,including switch in status to OTC
(conversion of prescription drug to OTC)

22. (I) Content and format of application
(Ii) formatting, assembling and submitting new
drug and antibiotic applications
(Iii) nda summary format and content
(Iv) nda technical sections

23. (I) CONTENT AND FORMAT OF
APPLICATION:
• Although the exact requirements are a function
of the nature of a specific drug, the NDA must
provide all relevant data and information that a
sponsor has collected during the product's
research and development.

24. (II) FORMATTING, ASSEMBLING AND SUBMITTING NEW DRUG AND
ANTIBIOTIC APPLICATIONS:
• A. APPLICATION FORMAT:
THE NDA REGULATIONS REQUIRE THE SUBMISSION OF
ARCHIVAL COPY.
REVIEW COPY.

25. 1. ARCHIVAL COPY:
• this is a complete copy of the application submission and is intended to
serve as a reference source for FDA reviewers. This contains information
which not contained in the review copy.
2. REVIEW COPY:
• It is divided into five (or six) sections containing technical and scientific
information required by FDA reviewers. Each section of the review copy
is separately bound. It should be provided with the following:
• a copy of the cover letter.
• a copy of the application form (FDA 356h)
• a copy of the overall summary
• A copy of the index to the entire application
• an index to the specific review section
• both copies are submitted in hard copy.

26. B.
ASSEMBLING THE APPLICATION:
1. FOLDER: because of the procedure used at the FDA to file and retrieve
material from the document rooms where applications are kept, it is
necessary that applicants use the colored folders to bind the archival
copy and each technical section. The cover of each folder should bear
the nda number (if known), name of the applicant, and name of the drug
product.
2. PAPER SIZE AND BINDING: all applications must be bound on the left side
of the page using the unite states standard size loose-leaf page.
(8.5″*11″).
3. pagination: all pages in the application must be numbered and numbering
of review copy pages should be same as the numbering of corresponding
pages in archival copy.

27. 4. volume size and identification: volume submitted in hard copy form
should be no more than 2 inches thick.
5. packing carton: the box size of 14″*12″*9.5″ is recommended for
shipment of applications to FDA. because andas are handled and
stored separately, smaller boxes may be appropriate for them.
6. supplements, amendments and post-marketing reports: the
submission format for amendments to pending applications and
supplements to approved applications will be the same as an original
application. Each submission will consist of two copies: a complete
archival copy and an appropriately segmented review copy.
Amendments, supplements, resubmissions annual reports, and other
correspondence concerning full applications should be addressed to
appropriate FDA reviewing divisions.

28. C. APPLICATION CONTENT:
archival copy: the archival copy is required to contain the
following: application form (fda 356h) it serves as a cover
sheet for the application and contains basic identifying
information about the applicant and the drug product. the
application form, as well as the index and the summary,
should be bound together in a single volume. patent
information on the applicant’s drug and a patent
certification with respect to the drug should be submitted
on a separate piece of paper attached to the application
form itself.

29. (III) nda summary format and content:
summary should provide sufficient detail. data should be provided in
tabular or graphical form. the summary should be between 50-
200 pages.
A. an annotated package insert:this section include the proposed
text of the labeling for the product. the proposed text of the
package labeling must be annotated by reference to volume
and page number to the information in the summary and in the
technical sections of the applications.
B. pharmacological class, scientific rationale, intended use and
potential clinical benefits: a brief statement should be included
to identify the pharmacological class of the drug, the scientific
rationale for the drug, its intended use, and its potential clinical
benefits

30. C. chemistry, manufacturing and controls:
this summary must provide overview of the drug
substances and the drug product.
1. drug substance:
it includes description about of drug substance, physical
and chemical characteristics and stability of the drug
substance.
2. drug product:
it includes information about:
a. composition and dosage form
b. name and address of manufacturer
c. container and closure system
d. stability
e. specifications for drug product and test methods to
assure the specifications

31. .D FOREIGN MARKETING HISTORY:
if the product is marketed outside the u.s., regardless of the dosage form,
strength, salt, ester, or complex of the drug, the marketing history should be
provided. this should include a list of countries in which drug product is
marketed, with dates of marketing, if known. it must also include a list of any
countries in which the drug has been withdrawn for any reason relating to
safety or efficacy. a specific reason for withdrawal should be given.
e.nonclinical pharmacology and toxicology summary: it includes information
about:
1. pharmacology studies
2. acute toxicity studies
3. multi-dose toxicity studies
4. carcinogenicity studies
5. special toxicity studies
6. reproduction studies
7. mutagenicity studies
8. adme studies

32. F. Human pharmacokinetics and bioavailability summary:
it includes a brief description about the bioavailability study of drugs,
pharmacokinetic characteristics of active ingredients and dissolution
profile of drug.
G. Microbiology summary:
it provides summary of results of the microbiologic studies conducted
with anti-infective and antiviral drug. This includes mechanism of
action, antimicrobial spectrum of action and mechanism of resistance
to the drug.
H. Clinical data summary and results of statistical analysis:
it is the basis of efficacy and safety that will determine an NDA
approval. The clinical data summary and results of statistical analysis
are divided into several parts as described below:
Clinical pharmacology
Overview of clinical studies
Controlled clinical studies
Uncontrolled clinical studies
Other studies and information
Safety summary (general safety conclusions).

33. (IV) NDA technical sections:
This includes brief description of the following sections.
Chemistry, manufacturing and controls: it is the most critical portion
of nda or anda . this section must fully describe the composition
of the drug substance (active ingredient), and its synthesis (or
isolation) and purification, as well as application process
controls, specifications, and analytical test methods.
B. Nonclinical pharmacology and toxicology: it provides a description
or summary of all animal and in-vitro studies with the drug.
1. Pharmacology studies:
2. Acute toxicity studies:
3. Subchronic/chronic/carcinogenicity studies:
4. Special toxicity studies
5. Reproduction studies
6. Mutagenicity studies
7. ADME studies

34. Human pharmacokinetics and bioavailability section:
For a new chemical entity (NCE), it is desirable to determine its
bioavailability and pharmacokinetics from the dosage form, except
that for certain dosage forms (e.G., Iv solutions) 100%
bioavailability may be assumed.
For solid oral dosage forms (e.G., Capsule or tablet) a bioequivalence
study is often necessary to demonstrate that formulation proposed
for marketing is bioequivalent to whatever formulations may have
been employed in an early clinical trial.
The summary should include a table with the following
pharmacokinetic parameter: cmax,auc, tmax, kel, vd, plasma and
renal clearance and urine excretion.
D. Microbiology: this section is of major importance for anti-infective
drugs and includes data on the biochemical basis of the drug’s
action and its antimicrobial spectra; any known mechanisms of
resistance to the drug; and clinical laboratory methods.

35. E. Clinical data section:
it is the most important and most complicated section of an NDA. It is the part
that provides the safety and efficacy data on the drug for its intended use.
F. Outline of clinical section:
It includes:
1. List of investigators; list of inds and ndas
2. Background / overview of clinical investigations
3. Clinical pharmacology
4. Controlled clinical studies
5. Uncontrolled clinical studies
6. Other studies and information
7. Integrated summary of efficacy
8. Integrated summary of safety
9. Drug abuse and overdosage information
10. Integrated summary of benefits and risk of drugs

36. I. Patent information:
the information must be submitted regarding any
patent held by the sponsor that covers the drug substance,
formulation, and composition of the drug product, or
method of use. Upon approval of the NDA, this information
is published in the fda’s orange book (known formally as
approved drug products with therapeutic equivalence
evaluations) and serves as a guide to firms wishing to
develop generic copies of the innovator’s product