Regulatory approval of NDA, ANDA, and IND Guided by Dr.Yogannada R Professor and Head Dept of Pharmacy Practice SJM College of Pharamcy Chotardurga

1. IND, NDAAND
ANDA
DRUG EVOLUTION PROCESS
Guided by,
Dr. Yogananda R
Professor and Head
Dept. of Pharmacy Practice
SJMCP
Presented by,
Maruthi N
I M Pharm
Dept. of Pharmaceutics
SJMCP
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2. • 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.
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3. 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.
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4. • 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.
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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.
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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. 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.
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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).
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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.
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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.
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10. 10
IND chart

11. Criteria for IND application
• 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.
A clinical study is required for an IND if it is intended to
support :
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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
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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.
9. Additional Information.
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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.
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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.
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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.
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17. After receiving the application, the
Central drug standard control
organization(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.
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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.
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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
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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.
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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) 21

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)
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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
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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.
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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
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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 inspect sample of clinical trial locations
to verify the accuracy of data submitted.
iv. Microbiology (if required)
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27. 27
NDA chart

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.
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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.
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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 DCGI
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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.
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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.
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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 demonstrate
Bioequivalence to Innovator (brand name) drug
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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.
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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 format.
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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
• Dosage form and Strength
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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.
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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.
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39. 39
ANDA Chart

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 DESI
(Drug efficacy study implementation).
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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
• Patent Challenge----------180 days.
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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.
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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.
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44. 44

45. Reference
• http://www.fda.gov/RegulatoryInformation/Gu
idances/ucm129703.htm
• World Journal of Pharmaceutical Research
;SJIF Impact Factor 5.045; Volume 3, Issue 6,
406-411.Review Article ISSN 2277 – 7105
• www.slideshare.com
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46. THANK YOU
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