Global submission of ind, nda, anda

Global Submission of IND, NDA, ANDA
Mohammad Khalid
Associate Professor
Krishna Pharmacy College, Bijnor

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.
3 February 2022 MOHAMMAD KHALID

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.

The sponsor submits the application for conduct 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.

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.

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.

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.

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:
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.

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.
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).

The IND application must contain
information in 3 broad areas:
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.
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.

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.

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.

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.

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, immunocompromised)
Significant change in the promotion of an
approved drug.

3 February 2022
MOHAMMAD KHALID

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.
9. Additional Information.

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.

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

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.

After receiving the
application, the Central drug
standard control organization
(CDSCO) Headquarters in
New Delhi refers 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.

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.

NEW DRUG
APPLICATION
(NDA)

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

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.

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)

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)

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

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.

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

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.

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. 3 February 2022 MOHAMMAD KHALID

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.

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

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.

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.

ABBREVIATED NEW DRUG
APPLICATION (ANDA)

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.

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

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.

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

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

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.

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

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
Patent Challenge----------180 days.

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.

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.

Global submission of ind, nda, anda

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