Global submission of IND, NDA ANDA ( Santosh Kumar) (1).pptx
1. Global
submission of
INDs, NDA &
ANDA
Presented by-
Santosh Kumar
M.Pharm Pharmaceutics
1st semester
Presented to-
Dr. Vijay Kumar MR
Department of Pharmaceutics
BBAU Lucknow
2. Content
✓ Investigational New Drugs (INDs)
Introduction
Types of INDs
Format and content of INDs
IND process in India
✓ New Drug Application (NDA)
Classification of NDA
Format and content of NDA
General requirements for filing NDA
NDA process in India
✓ Abbreviated New Drug Application (ANDA)
Introduction
Format and content of ANDA
✓ Difference between NDA & ANDA
✓ References
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3. Introduction
• 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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5. 5
✓ Investigational New Drug is defined 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.
6. 6
• 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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✓ 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.
8. • COMMERCIAL INDS:
✓ These are applications that are submitted primarily by
the companies to obtain marketing approval for a new
product.
• NON-COMMERCIAL (Research) INDs:
✓ These INDs are filed for non-commercial 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. 8
Types of Investigational new drugs (INDs)
9. 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 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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• 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.
11. Format & content of IND
✓ Cover sheet ( Form FDA 1571).
✓ A table of contents.
✓ Introductory statement and General Investigational
Plan.
✓ Investigator's Brochure.
✓ Protocols.
✓ Chemistry, Manufacturing and Control information.
✓ Pharmacology and Toxicology Information.
✓ Previous human experience with IP.
✓ Additional Information.
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12. 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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• 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 I8. Regulatory
status in other countries as per Appendix I.
• 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.
16. ✓ 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.
✓ 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 16
17. ✓ 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) 17
Classification of drugs in NDA
18. ✓ 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 NDAD.
Supplemental New Drug Application (SNDA)
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✓ 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 I to 5)
iv. Summary
v. Chemistry, Manufacturing and Control
vi. Samples, Method Validation Package and
Labeling
Format & content of NDA
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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.
21. 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. Non clinical Pharmacology
and Toxicology iii. Human Pharmacokinetics
and Bioavailability iv. Microbiology (if
required)v. Clinical data vi. Statistical
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23. 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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d) All vaccines are considered as new drug
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.
26. ✓ Generic drug applications are referred to Abbreviated
New Drug Application.
✓ Pharmaceutical companies must admit ANDs 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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27. ✓ 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.
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28. 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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29. ✓ 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:
✓ •Paragraph I Certification- That the patent information
has not been submitted to FDA.
✓ •Paragraph II Certification- That the patent has expired
✓ •Paragraph III Certification- That the patent will expire
(on date of marketing)
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30. ✓ • Paragraph IV Certification- That
the patent is invalid,
unenforceable, or will not be
infringed by the manufacture,
use, or sale of generic drug.
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32. Difference between submission of NDA & 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 AND 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). 32
