Abbreviated New Drug Application, Investigational Medicinal Product Dossier & Investigation Brochure.

1. Presented by : Mr. Pradipkumar G. Rathod
M. Pharm 1st year (1st sem.) (Pharmaceutics).
UNIVERSITY DEPARTMENT OF PHARMACEUTICAL SCIENCES,
R.T.M. NAGPUR UNIVERSITY, NAGPUR.
Abbreviated New Drug Application (ANDA),
Investigational Medicinal Product Dossier
(IMPD) & Investigation brochure (IB)

2. 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

3.  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.

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.

5.  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.

6. 3 copies of abbreviated application are required to be submitted
 An archival copy
 A review copy
 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

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:
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.

8. Applicant
Preapproval
inspection results
ok ?
ANDA
Request for plant
inspection
Application
review
“Refuse to
receive”
letter
Acceptable
and
complete
Approved
ANDA
Bioequivalenc
e review
Labelling
Review
Chemistry
and micro.
review
Not approvable
letter
Bio
deficiency
letter
Chem./micro
ok?
Labelling
ok ?
Bioequivalenc
e ok?
N
Y
Approval
withheld until
results
satisfactory
N N
N

9. • 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
• Paediatric Exclusivity--------6 months additional
• Patent challenge-----------180 days

10.  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.

11.  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.

12. Hatch Waxman Amendment Benefits
To Innovator’s Companies To generic drug companies
45 days to claim
To challenge Patent drug
Delayed for 30 months
If suit
Not
Suit
180 day exclusivity period

13.  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.

14.  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)

15.  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.

16.  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

17.  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.

18.  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.

19.  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.

20. 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.

21. 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.

22. 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.

23. 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;
- Dose response.

24. 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.

25. 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).

26. 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.

27. 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.

28. 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.

29. Thank you!