This document provides an overview of regulatory affairs processes for new drugs, including Investigational New Drug (IND) applications, New Drug Applications (NDA), and Abbreviated New Drug Applications (ANDA). It defines these terms and describes the required contents, format, review process and differences between IND, NDA, and ANDA submissions to regulatory agencies like the FDA. Key points covered include the types of clinical trials and data required for each application and how generic drugs can demonstrate bioequivalence rather than conducting new clinical trials in an ANDA.

1. Presentation by : Pawankumar Hanamant Yadav
1st year M. Pharm (sem –l)
Dept. : Pharmaceutics
Guided by : Prof. K.J. Kore
Subject : Regulatory Affairs
RAJGAD DNYANPEETH’s
COLLEGE OF PHARMACY , BHOR

2. Contents:
• IND (INVESTIGATIONAL NEW DRUG)
• NDA (NEW DRUG APPLICATION)
• ANDA(ABBREVIATED NEW DRUG APPLICATION)

3. INVESTIGATIONAL NEW DRUG:
• Investigational New Drug is defined under 21 CFR
312.3(b) as ‘ a new drug or biological drug that is
used in clinical investigation’.
• The term also includes a biological product used in
vitro for diagnostic purposes.
• After pre-clinical investigations when the new
molecule has been screened for pharmacological
activity and acute toxicity potential in animals the
sponsor requires permission from FDA for its clinical
trials in humans.

4. of
human clinical trials called Investigational New
Drug
(IND) application to FDA or DCGI .
• Once IND application is submitted , the sponsor
must wait for 30 days before initiating any clinical
trial.
• Clinical trials in humans can begin only after IND
is
reviewed by the FDA and a local institutional
review
board (IRB).
• IRBs approve clinical trial protocol, informed
consent of all participants and appropriate steps to
prevent subjects from harm.

5. • If the FDA accepts the IND request within 30 days of
submission, clinical testing of the new molecule on human
may begin by the investigator.
• At this point, the molecule under the legal status of FDA
becomes a new drug subject to specific requirements of
drug regulatory system.
• If at any time during clinical testing, the data furnished
to FDA indicate the IP to be toxic under the criterion of
FDA’s Benefit/Risk ratio, FDA can terminate clinical
trial and its actions are not subject to any judicial
review.

6. Types Of INDs
A. COMMERCIAL INDs
• These are applications that are submitted primarily by the
companies to obtain marketing approval for a new product.
B. NON COMMERCIAL (Research)INDs
• These INDs are filed for noncommercial research.
These are :
1) Investigator’s IND- It is submitted by a physician who both
initiates and conducts an investigation and who also administers
and dispenses the IP. A physician might submit a research IND to
propose studying an unapproved drug or an approved drug for
new indications or in new patient population.

7. 2) Emergency Use IND-
This IND allows FDA to allow the use of an experimental
drug in an emergency situation that does not allow
submission of an IND in accordance with 21 CFR
Sec312.23 or Sec 312.34.
It can also be used for patients who do not meet the criteria
of an existing study protocol or if an approved study
protocol does not exist.
3) Treatment IND- Also called Expanded Access IND this
IND may be submitted for experimental drugs showing
promise in clinical testing of serious and immediately life
threatening conditions while the final clinical work is
conducted and the FDA review takes place (21 CFR
312.34).

8. • The IND application must contain information in 3
broad areas:
i. Animal Pharmacology and toxicology studies-
Preclinical data to assess if the product is reasonably safe
for initial testing in humans. Also , included are any
previous with drug in humans.
ii. Manufacturing information- Information pertaining to
composition, manufacturer, stability and controls used for
manufacturing drug product to ensure that the company
can adequately produce and supply consistent batches of
the drug.

9. iii. Clinical Protocol and Investigator information
• Detailed protocols for proposed clinical studies to make
sure subjects are not exposed to undue risks. Also,
information on the qualifications of the investigators
(chiefly physicians) if they fulfill their clinical duties.
• Finally, commitments to obtain informed consent from
all research subjects, to obtain review of the study by an
IRB and to adhere to the investigational new drug
regulations.
• An IND must also include The Investigator’s
brochure.

11. Criteria for IND application
A clinical study is required for an IND if it is intended to
support :
• A new indication
•Change in the approved route of administration or dosage
level.
• Change in the approved patient population (vulnerable
subjects e.g. pediatrics, elderly, HIV +ve, immuno
compromised)
• Significant change in the promotion of an approved drug.

12. Code of federal regulations (cfr)

13. Format and content of IND
1.Cover sheet ( Form FDA1571).
2.A table of contents.
3.Introductory statement and General Investigational Plan.
4.Investigator’s Brochure.
5.Protocols.
6.Chemistry, Manufacturing and Control information.
7.Pharmacology and Toxicology Information.
8.Previous human experience with IP.
9.Additional Information.

14. WITHDRAWAL OF an IND
• At any time a sponsor can withdraw an effective
IND
. In such a case, FDA and IRB shall be so notified
with reasons for withdrawal, all clinical studies
ended, all current investigators and subjects
notified, all stocks of drug returned to the sponsor
or otherwise disposed off on request of sponsor in
accordance with 312.59.

15. IND PROCESS IN INDIA
• IND has been defined under Rule 122-DA (3) of Drugs
and Cosmetics Rules 1945 as a chemical entity having
therapeutic indication but which have never been earlier
tested on humans.
• No clinical trial for new drug for any purpose be
conducted without permission , in writing, of the Licensing
Authority (DCGI).
• Application for conducting clinical trials in India require
submission by the sponsor on Form 44 along with requisite
fee (Rs 50k) and documents as provided under Schedule Y
to Drugs and Cosmetics Act 1940.

16. • Data to be submitted along with the application on
Form44 to conduct clinical trials (2 hard copies and 2 soft
copies i.e., CDs in PDF format)
1. Application on Form 44
2. Introduction of the drug
3. Fee Rs 50K through challan form
4. Chemical and Pharmaceutical information as per
Appendix I of Schedule Y
5. Animal Pharmacology as per Appendix IV
6. Animal Toxicology as per Appendix III
7. Human/Clinical Pharmacology data as per Appendix I
8. Regulatory status in other countries as per Appendix I.

18. • It takes 4-6 months for the approval but it is not
documented. The Ethical Committee also requires
1-3 months time. Thus , it almost takes 7-9 months
for approval of INDA from DCGI.
• For international applicants, import license to
import IP samples and permission from Director
General Foreign Trade to export blood samples is
also needed.

19. NEW DRUG APPLICATION (NDA)
• The New Drug Application is the vehicle through which
the drug sponsors formally propose FDA or DCGI to
approve a new investigational drug for sale and marketing
after Phase IIIA Pivot trials.
• The official definition of New Drug is in Sec 201(p) of
Federal Drug, Food and Cosmetics Act as;
•Any new drug , the composition of which is such that it is
not recognized among experts qualified by scientific
training as safe and effective for use under prescribed,
recommended or suggested conditions

20. • Any drug the composition of which is such that it as a
result of investigations to determine safety and efficacy for
use has become recognized, but which has not, otherwise in
such investigations been used to a material extent .
• The following letter codes describe the review priority of
the drug;
• S-Standard review: For drugs similar to currently
available drugs
• P-Priority review: For drugs that represent significant
advances over existing treatments.

21. Classification of drugs in NDA
• Center of drug evaluation and Research(CDER) classifies
new drug applications according to the type of drug being
submitted and its intended use:
a. New molecular entity
b. New salt of previously approved drug
c. New formulation of previously approved drug
d. New combination of two or more drugs
e. Already marketed drug product- Duplication (i.e., new
manufacturer)
f. New indication (claim) for already marketed drug
(includes switching marketing status from prescription
to OTC)
g. Already marketed drug product ( no previous approved
NDA)

22. • In US following 4 types of applications are submitted for
approval of drug for marketing depending upon the type
and nature of the drug:
A.New Drug Application (NDA)
B.Biological License Application (BLA)
C.Application u/s 505(b)(2)-Paper NDA
D.Supplemental New Drug Application (SNDA)

23. Format and content of NDA
• The application is required to be submitted in common
technical document format with the following different
sections:
i. FDA Form 356h
ii. User Fee Cover Sheet (FDA Form 3397)
iii. Cover letter (Comprehensive table of contents for
Modules 1to 5)
iv. Summary
v. Chemistry, Manufacturing and Control
vi. Samples, Method Validation Package and Labeling.

24. vii. Nonclinical Pharmacology and Toxicology
viii. Human Pharmacokinetics and Bioavailability
ix. Microbiology (For anti-microbial drugs only)
x. Statistical methods and analysis of Clinical Data
xi. Safety Update Report (typically submitted 120 days
after NDA submission)
xii. Statement regarding compliance to IRB and Informed
Consent requirements
xiii. Case Report Tabulations
xiv. Case Report Forms
xv. Patent information and certification
xvi. Other information.

25. General requirements for filing NDA
• The new NDA regulations require the application to be
submitted in 2 copies:
A.An Archival Copy- It is a complete copy of application
submission that serves as its permanent record.
B. A Review Copy-It is divided into 6 technical sections:
i. Chemistry , Manufacturing and Controls (CMC)
ii. Nonclinical Pharmacology and Toxicology
iii. Human Pharmacokinetics and Bioavailability

26. iv) Microbiology (if required)
v) Clinical data
vi) Statistical
•On receipt of NDA, the CDER stamps with a receipt date
to enable FDA to forward action within 180 days called
‘Review Clock’ under Review Time Frames (21CFR
314.1OO). The FDA assigns the application for review.
The FDA has to intimate the applicant if it is incomplete
within 60 days according to Filing Time Frames (21CFR
314.101). FDA notifies the sponsor of its completion/
incompletion and if complete sends it for secondary review
process. FDA inspects the manufacturing facilities for the
drug, It may also inspect sample of clinical trial locations
to verify the accuracy of data submitted.

28. NDA PROCESS IN INDIA
• In India, New Drug is defined under Rule 122-E of
Drugs and Cosmetics Act as:
a) A drug which has not been used in the country to any
significant extent under various conditions
b) A drug already approved by DCGI for certain claims
which is now proposed to be marketed with new claims
like indications, dosage, dosage form etc.
c) A fixed dose combination of two individually approved
drug being combined for the first time in a fixed ratio or
new ratio in already marketed combination.

29. d) All vaccines are considered as new drugs.
e) A new drug continues to be considered as new drug for
a period of 4 years from its approval or its inclusion in
Indian Pharmacopoeia.
•After successful finishing of clinical trials, the applicant
seeking for approval to manufacture a new drug requires to
submit application on Form 44 along with data as given in
Appendix I to Schedule Y of Rules 1945 to DCGI who
grants its approval in Form 46 or 46-A.
•Further, the applicant is required to submit evidence that
the drug for manufacturing approval has already been
approved by DCGI

30. • In his name while applying to manufacture a
new drug to State Licensing Authority.
Thus the applicant is required to obtain necessary
approval from DCGI as well as SLA for
manufacturing a new drug for sale purposes in
India.
• The approval issued is ‘manufacture for sale’
rather than ‘marketing approval’ as per the
practice world over.

31. PERMISSION TO MANUFACTURE a NEW
DRUG
• Brief introduction of the new drug
• Chemical and pharmacological information
• Animal pharmacology and Toxicology
• Human/ Clinical Pharmacology (Phase I)
• Exploratory Clinical Trials (Phase II)
• Confirmatory Clinical Trial s(Phase III)
• Bio-availability, dissolution and stability study data
• Regulatory status in other countries
• Application for test license
• Marketing information.

32. ABBREVIATED NEW DRUG APPLICATION
(ANDA)
• Generic drug applications are referred to Abbreviated New
Drug Application.
• Pharmaceutical companies must admit ANDAs and
receive FDA’s approval before marketing new generic drugs
according to 21CFR 314.105(d).
• Once ANDA is approved, an applicant can manufacture
and market generic drug to provide safe, effective and low
cost alternative of innovator drug product to the public.
• Generic drugs are termed ‘abbreviated’ as they are not
required to include preclinical and clinical data to establish
safety and efficacy. They must scientifically demonstrate
Bioequivalence to Innovator (brand name) drug.

33. • A generic drug is comparable to Innovator drug I
dosage form, strength, route of administration, quality,
performance and intended use.
• One of the ways to demonstrate bioequivalence is to
measure the time taken by generic drug to reach
bloodstream in 24-36 healthy volunteers. The time and
amount of active ingredients in the bloodstream should
be comparable to those of Innovator drug.
• Use of bioequivalence as base for approving generic
drug products was established in 1984, also known as
WAXMAN-HATCH ACT. It is because of this act that
generic drugs are cheaper without conducting costly and
duplicative clinical trials.

34. CODE OF FEDERAL REGULATIONS
• The following regulations apply to ANDA process:
• 21 CFR 314- Applications for FDA approval to market
a New Drug or Antibiotic Drug
• 21 CFR 320- Bioavailability and Bioequivalence
requirements
• 21 CFR 310- New Drugs.
•Office of Generic Drug(OGD) strongly encourages
submission of bioequivalence, chemistry and labeling
portions of the application in electronic format.

35. FORMAT AND CONTENT OF ANDA
• 3 copies of the Abbreviated application are required to
be submitted; an archival copy, a review copy and a
field copy. An Archival copy shall contain the
following:
• Application form
• Table of Contents
• Basis for ANDA submission
• Conditions of use
• Active Ingredients
• Route of Administration
• Dosage form and Strength

36. • Bioequivalence and Bioavailability
• Labeling
• Chemistry, Manufacturing and Controls
• Samples
• Patent Certification
• Financial Certification or disclosure statement.
• Other Information.
•Under Sec 314.94 (a) (12), the patent certification
includes one of the following:
I. Paragraph I Certification- That the patent information
has not been submitted to FDA.

37. II. Paragraph II Certification- That the patent has expired
III. Paragraph III Certification- That the patent will expire
(on date of marketing)
IV. Paragraph IV Certification- That the patent is invalid,
unenforceable, or will not be infringed by manufacture, use
or sale of generic drug.

39. Difference between submission of NDA and ANDA
•NDA requires submission of :
1. Well-controlled clinical studies to demonstrate
effectiveness.
2. Preclinical and clinical data to show safety.
3. Details of Manufacturing and Packaging.
4. Proposed annotated Labeling
• In contrast ANDA requires submission of :
1. Detailed description of components.
2. Manufacturing, Controls, Packaging, data to assure
bioequivalence and bioavailability and Labeling. Labeling
should be prepared in accordance with DESI (Drug efficacy
study implementation).