IND, NDA AND

ANDA
 The Federal Food, Drug and Cosmetics act regulated
through Title 21 of U.S Code of federal Regulations,
requires a new drug to be approved by FDA before
legally getting introduced into the market.
 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.
 INVESTIGATIONAL NEW DRUG (IND)
• 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.
 Ifthe 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.
 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. 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.
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).
 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.
 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.
 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.
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 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.
 Ittakes 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)
• 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.
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 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
 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.
 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.
 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
 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.
 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 :
 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).
 40
 EXCLUSIVITY
• Exclusivity is a statutory provision designed to promote
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.