2. The Federal Food, Drug and Cosmetics act regulated
through Title 21 of U.S Code of federal
Regulations(CFR), Before introduction into the
market a new drug needs to be approved by FDA
In India, a new drug may be approved as regulated by
Schedule Y to the Rules of Drugs and Cosmetics
Act, 1940 and Rules 1945.
3. INVESTIGATIONAL NEW DRUG (IND)
1. Investigational New Drug is defined under 21 CFR
312.3(b) as ‘a new drug or biological drug that is used in
clinical investigation’.
2. The term also includes a biological product used in vitro
for diagnostic purposes.
3. After pre-clinical investigations when the new molecule
has been screened for pharmacological activity and
acute toxicity potential in animals
4. Then, the sponsor requires permission from FDA for its
clinical trials in humans.
4. 5. The sponsor submits the application for conduct of
human clinical trials called Investigational New Drug
(IND) application to FDA.
6. Once IND application is submitted, the sponsor must
wait for 30 days before initiating any clinical trial.
7. Clinical trials in humans can begin only after IND is
reviewed by the FDA and a local institutional review
board (IRB).
8. IRBs approve clinical trial protocol, informed
consent/permission to all the participants and
appropriate steps to prevent subjects from harm.
5. 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.
6. At this point, the drug molecule under the FDA
legally which requires specific drug regulatory
system.
7. If at any time during clinical testing, the data
furnished to FDA indicate 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. NONCOMMERCIAL (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.
7. 2) Emergency Use IND-
FDA allows the use of an experimental drug in an
emergency situation.
It does not allow submission of an IND in accordance
with 21 CFR Sec312.23 or Sec 312.34.
It used for patients who do not meet the criteria of an
existing study protocol or if an approved study protocol
does not exist.
2) Treatment IND- (Expanded Access IND)
- submitted for experimental drugs
Shows promise in clinical testing of serious and
immediately life threatening conditions.
8. The IND application must contain information in
3 broad areas:
i. Studies of Animal Pharmacology and
toxicology -Preclinical data to assess if the
product is reasonably safe for initial testing 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:-
Information on the qualifications of the investigators
(chiefly physicians) if they fulfill their clinical duties.
Finally, from all research subjects the commitments
is obtained for review of the study by an IRB and
to adhere to the investigational new drug
regulations.
An IND must also include in the Investigator’s
brochure.
11. CRITERIA FOR IND APPLICATION
• A new indication/suggestion
• Change in the approved route of administration or
dosage level.
• Change in the approved patient population (vulnerable
subjects e.g. pediatrics, elderly, HIV +ve,
immunocompromised)
• Significant change in the promotion of an approved
A clinical study is required for an IND if it
is intended to support :
12. CODE OF FEDERAL REGULATIONS (CFR)
• Investigational new drug application.21CFR PART 312
• Institutional review boards.21CFR PART 56
• INDA and NDA for FDA approval to
market a new drug.
21CFR PART 314
• Orphan drugs21CFR PART 316
• Good lab practice for Nonclinical
laboratory (animal) studies.21CFR PART 58
• Protection of human subjects.21CFR PART 50
• Drug labeling.21CFR PART 201
• Financial disclosure by clinical
investigator.21CFR PART 54
13. FORMAT AND CONTENT OF IND
1.Cover sheet ( Form FDA 1571).
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.
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.
17. After receiving the
application, the CDSCO
Headquarters in New
Delhi refer it to
The New Drug division
where it is reviewed by
IND committee. The
Committee submits its
report to
To DCGI along with its
recommendations. If the
report by Committee is
favorable, DCGI
approves the INDA.
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 OR
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
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
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 1 to 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. 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
iv. Microbiology (if required)
28. Throughout the process FDA and sponsor
communicate through in person meetings,
telephone conferences, fax etc. to seek
clarification if necessary. Once all reviews
are complete; the Divisional Director
evaluates the reviews and makes FDA’s
decision. The FDA may:
• Approve the drug for marketing.
• Approve the drug with condition when
problem exist with the application that
needs to be addressed before approval.
• Refuse to approve the drug, when it may
require additional research or
reformulation of the drug product.
29. 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.
30. 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
31. 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.
32. 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.
33. 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
34. 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.
35. 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
36. 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
37. • 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.
38. 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.
40. 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
41. EXCLUSIVITY
Exclusivity is a statutory provision
designed to promote a balance between
an Innovator and Generic drug
competitor. As long as a drug patent
lasts , a reference listed drug company
enjoys a period of market exclusivity or
monopoly. Expiration of patent removes
the monopoly of the patent holder.
TERMS OF EXCLUSIVITY
Orphan drugs---------- 7 years
New Chemical Entity----------5 years
Pediatric Exclusivity---------6 months
additional
42. HATCH-WAXMAN AMENDMENTS AND 180 DAYS
EXCLUSIVITY.
Before Hatch Waxman Amendment, generic
manufacturer could file ANDA only after
innovator’s patent expiry or cancellation.
But under Sec 505(j)(5)(B) of Hatch
Waxman amendment it permits
preparation and filing of ANDA before
patent expiration, so that the effective
approval date of generic drug would be
on expiration date of the patent of
Innovator Original drug.
The Act also establishes another procedure
in which the generic company can
challenge patent of the Innovator.
43. For generic companies, the amendment
provide an inventive 180-day exclusivity
period in which no other ANDA for that
drug can be approved. This 180-day
period is to encourage generic
companies to challenge validity of
Orange book listed patents or to design
around these patents to bring more
quickly a generic drug to market.
For Innovator company, filing of an ANDA
is an act of patent infringement. So, if
innovator company brings suit within 45
days, the approval of generic company’s
ANDA is delayed for upto 30 months.
