Introduction to ANDA Regulations applied to ANDA process Format and content of ANDA ANDA approval process Exclusivity Hatch-Waxman amendments & 180 days exclusivity Introduction to IMPD Contents of IMPD Introduction to IB Contents of IB

1. S.GOKULAKRISHNAN
M.Pharm (Pharmaceutics) – I Year,
Mother Theresa Post Graduate and Research Institute of
Health Sciences,
Govt of Puducherry
Puducherry.
NON CLINICAL DRUG DEVELOPMENT
NON CLINICAL DRUG DEVELOPMENT 1
ANDA

2. CONTENTS
 Introduction to ANDA
 Regulations applied to ANDA process
 Format and content of ANDA
 ANDA approval process
 Exclusivity
 Hatch-Waxman amendments & 180 days exclusivity
 Introduction to IMPD
 Contents of IMPD
 Introduction to IB
 Contents of IB
NON CLINICAL DRUG DEVELOPMENT 2

3. INTRODUCTION TO ANDA
Generic drug applications are referred to Abbreviated New
Drug Application.
Pharmaceutical companies must admit ANDAs and receive
FDAs approval before marketing new generic drugs according
to 21CFR 314.105(d).
Once ANDA is approved, an applicant can manufacture and
market generic 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.NON CLINICAL DRUG DEVELOPMENT 3

4. A generic drug is comparable to innovator drug 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.NON CLINICAL DRUG DEVELOPMENT 4

5. REGULATIONS APPLIED TO ANDA PROCESS
 21 CFR 314- Applications for FDA approval to market a new drug
or antibiotic drug.
 21 CFR 320- Bioavailability and bioequivalence requirement.
 21 CFR 310- New drugs.
 Office of Generic Drugs (OGD) strongly encourages submission
of bioequivalence, chemistry and labelling portions of the
application in electronic format.
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6. FARMAT AND CONTENT OF ANDA
o3 copies of abbreviated application are required to be submitted
 An archival copy
 A review copy
 A field copy
1.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 strengthNON CLINICAL DRUG DEVELOPMENT 6

7.  Bioequivalence and Bioavailability
 Labelling
 Chemistry, Manufacturing and controls Samples
 Patent certification
 Financial certification
 Other Information if any.
UNDER SECTION 314.98 (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).
 PARAGRAPH IV CERTIFICATION : That the patent is invalid,
Unenforceable, or will not be infringed by manufacture, use or sale of
generic drug. NON CLINICAL DRUG DEVELOPMENT 7

8. HATCH-WAXMAN AMENDMENTS & 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 the patent of Innovator Original drug.
 The act also establishes another procedures in which the
generic company can challenge patent of the Innovator.
NON CLINICAL DRUG DEVELOPMENT 8

9.  For generic companies, the amendment provide an inventive 180-
days exclusivity period in which no other ANDA for that drug can
be approved. This 180-days 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 bring suit within 45 days,
the approval of generic company’s ANDA is delayed for upto 30
months.
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10. HATCH WAXMAN AMENDMENT BENEFITS
NON CLINICAL DRUG DEVELOPMENT 10
TO GENERIC DRUG COMPANIESTO INNOVATOR’S COMPANIES
180 DAY EXCLUSIVITY PERIOD45 DAYS TO CLAIM
TO CHALLENGE PATENT DRUGIF SUIT NOT SUIT
DELAYED FOR 30 MONTHS

11. INTRODUCTION TO IMPD
 The investigational Medicinal Product Dossier is the basis for approval of clinical trials by
the competent authorities in the EU.
 The clinical trial directive (2001/20/EC) came into force in April 2001, harmonizing the
laws, regulations and administrative provisions of the member states relating to the
implementation of Good Clinical Practice (GCP) in the conduct of clinical trials on
medicinal products for human use.
 The directive introduced a harmonized procedure for the authorisation to perform a
clinical study in any one of the EU member states.
 In addition, it declines the documentation to be submitted to the Ethics committee as well
as the investigational Medicinal Product Dossier (IMPD) to be submitted to the competent
authority for approval.
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12. Before human clinical trials can be started in the European
Union (EU), the sponsor must request authorization to
conduct clinical trials through a submission called a Clinical
Trial Authorization (CTA). This application includes a group
of scientific documents called as Investigational Medicinal
Product dossier (IMPD)
NON CLINICAL DRUG DEVELOPMENT 12

13. TYPES AND CONTENTS OF IMPD
The EU has provided for two types of IMPDs, a “Full IMPD” and a
“Simplified IMPD”, based on whether the product has been
described previously in another CTA or a marketing authorization
application.
Guidance on the structure and content of an IMPD is provided by the
European Commission (EC) in ENTR/F2/BL D(2003) CT1 Revision
2, dated October 2005. The IMPD consists of a group of documents,
with cross references to other documents, such as the investigator’s
brochure, the clinical protocol, or another IMPD.
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14. The IMPD has a general structure:
Quality (Chemistry, Manufacturing and Controls) data
Non-clinical Pharmacology and toxicology data
Previous clinical trial and human experience data
Overall risk and benefit assessment
FULL IMPD contents include
 Basic data on clinical study
 Clinical objectives
 Vectors description
 Manufacturing, Supply and Import
 Preclinical DATA and risk assessment
 Patient & Informed Consent NON CLINICAL DRUG DEVELOPMENT 14

15. It is compilation of the clinical and nonclinical data on the investigational
product(s) that are relevant to the study of the product(s) in human subjects.
Its purpose is to provide investigators and others involved in the trials with the
information to facilitate their understanding of the rationale for, and their
compliance with , many key features of the protocol, such as the dose, dose
frequency/interval, methods of administration: and safety monitoring procedure.
The information should be presented in a concise, simple, objective, balanced,
and non-promotional form that enables a clinician, or potential investigator, to
understand it and make his/her own unbiased risk-benefit assessment of the
appropriateness of the proposal trial.
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16. INTRODUCTION TO IB
 The IB should be reviewed at least annually and revised as
necessary in compliance with a sponsor’s written procedures.
 Generally the sponsor is responsible for ensuring that an up to date
IB is made available to the investigator(s) and the investigators are
responsible for providing the up to date IB to the responsible
IRBs/IECs.
 In the case of investigator sponsored trial, the sponsor investigator
should determine whether a brochure is available from the
commercial manufacturer.
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17. If the investigational product is provided by the
sponsor-investigator, then he or she should provide the
necessary information to the trial personnel.
In cases where preparation of a formal IB is
impractical, the sponsor-investigator should provide, as
a substitute, an expanded background information
section in the trial protocol that contains the minimum
current information described in this guideline.
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18. GENERAL CONSIDERATIONS THE IB SHOULD
INCLUDE:
1. Title Page
This should provide sponsor’s name, the identity of each investigational product
i.e. research number , chemical or approved generic name, and trade name(s)
where legally permissible and desired by the sponsor, and the release date.
It is also suggested that an edition number, and a reference to the number and
date of the edition it supersedes, be provided.
2. Confidentiality statement
The sponsor may wish to include a statement instructing the investigators
/ recipients to treat the IB as a confidential document for the sole information and
use of the investigator’s team and the IRB/IEC.
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19. CONTENTS OF IB
The investigator brochure should include:
1.Table of Contents
2.Summary
A brief summary (preferably not exceeding two pages) should be given, highlighting the
significant physical, chemical, pharmaceutical, pharmacological, toxicological,
pharmacokinetic, metabolic, and clinical information available that is relevant to the stage of
clinical development of the investigational product(IP).
3.Introduction
Contains the chemical name (and generic and trade name(s) when approved) of the IP,
all active ingredients, the IP(s) pharmacological class and its expected position within this
class (e.g., advantages), the rationale for performing research with the IP(s), and the
anticipated prophylactic, therapeutic, or diagnostic indication(s).
General approach to be followed in evaluating the IP.
NON CLINICAL DRUG DEVELOPMENT 19

20. 4.Description of IP
A brief summary should be given of the relevant physical, chemical, and pharmaceutical
properties.
A description of the formulation(s) to be used, including excipient, should be provided and
justified if clinically relevant.
Instructions for the storage and handling of the dosage form(s) should also be given.
5.Nonclinical Studies
The results of all relevant nonclinical pharmacology, toxicology, pharmacokinetic, and
investigational product metabolism studies should be provided in summary form.
NON CLINICAL DRUG DEVELOPMENT 20

21. The information provided may include
Species tested;
Number and sex of animals in each group;
Unit dose (e.g., milligram/kilogram (mg/kg));
Dose interval;
Route of administration;
Duration of dosing;
Information on systemic distribution;
Duration of post-exposure follow-up;
Results, including the following aspects:
Nature and frequency of pharmacological or toxic effects;
Severity or intensity of pharmacological or toxic effects;
Time to onset of effects;
Reversibility of effects;
Duration of effects; NON CLINICAL DRUG DEVELOPMENT 21

22. 5.1 Nonclinical Pharmacology
A summary of the pharmacological aspects of the investigational
product and, where appropriate, its significant metabolites studied in
animals should be included.
5.2 Pharmacokinetics and Product Metabolism in Animals
A summary of the pharmacokinetics and biological transformation
and disposition (getting a drug into its appropriate position in the
body and in an appropriate concentration) of the investigational
product in all species studied should be given.
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23. 5.3 Toxicology
(The study of the adverse effects of chemicals on animals)
A summary of the toxicological effects found in relevant studies conducted in different
animal species should be described under the following headings where appropriate:
Single dose;
Repeated dose;
Carcinogenicity;
Special studies (e.g., irritancy and sensitization);
Reproductive toxicity;
Genotoxicity (mutagenicity). NON CLINICAL DRUG DEVELOPMENT 23

24. 6. Effects in Humans
A thorough discussion of the known effects of the investigational product(s) in humans
should be provided, including information on pharmacokinetics, metabolism,
pharmacodynamics,dose response, safety, efficacy, and other pharmacological activities.
Where possible, a summary of each completed clinical trial should be provided.
6.1 Pharmacokinetics and Product Metabolism in Humans
A summary of information on the pharmacokinetics of the investigational product(s) should
be presented, including the following, if available:
Pharmacokinetics (including metabolism, as appropriate, and absorption, plasma protein
binding, distribution, and elimination).
Bioavailability of the investigational product (absolute, where possible, and/or relative) using
a reference dosage form.
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25. Population subgroups (e.g., gender, age, and impaired organ function).
Interactions (e.g., product-product interactions and effects of food).
Other pharmacokinetic data (e.g., results of population studies performed within clinical
trial(s)).
6.2 Safety and Efficacy
A summary of information should be provided about the investigational product's
(including metabolites, where appropriate)safety , pharmacodynamics, efficacy, and dose
response that were obtained from preceding trials in humans (healthy volunteers and/or
patients).
6.3 Marketing Experience
The IB should identify countries where the investigational product has been marketed or
approved.
The IB should also identify all the countries where the investigational product did not receive
approval/registration for marketing or was withdrawn from marketing/registration.
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26. 7. Summary of Data and Guidance for the Investigator
This section should provide an overall discussion of the nonclinical
and clinical data of IP. IB provide the investigator a clear
understanding of The possible risk
Adverse reaction
Observation & precaution needed for the clinical trial.
NON CLINICAL DRUG DEVELOPMENT 26

27. REFERENCES
 21 CFR.org
 www.Wikipedia.org
 www.Cdsco.com
Drug regulatory affairs by thimasetty.Drug regulatory affairs by thimasetty.
19
 http://www.medicalnewstoday.com/
artes/172522.php