Investigational new drug application

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03/22/15 1
Investigational New Drug
Application (INDA)
www.PharmInfopedia.com


 INTRODUCTION
 REGULATORY ASPECT
 TYPE OF IND
 REQUIERMENT IND
 CONTENT OF IND
 IND AMENDMENT
 ANNUAL REPORT OF IND
 CONCLUSION
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WHAT I WILL TELL


What is INDA
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General introductionGeneral introduction
this data and information is generated andthis data and information is generated and
gathered from three broad areas:gathered from three broad areas:
Animal P’cology & Toxicology studiesAnimal P’cology & Toxicology studies
Manufacturing informationManufacturing information
Clinical Protocols & InvestigatorClinical Protocols & Investigator
InformationInformation


 The regulations in 21 CFR 312 cover procedures
and requirements for Investigational New Drug
Applications (INDs)
 These regulations define the roles and
responsibilities of FDA reviewers, IND sponsors,
and clinical investigators
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Regulation

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Sponsor
 A sponsor is an individual, company, institution, or
organization that takes responsibility for and
initiates a clinical study (21 CFR 312.3(b), 312.50)
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Definitions


A sponsor is responsible for:
 Selecting qualified investigators
 Ensuring study monitoring
 Maintaining an effective IND, and
 Ensuring AE risk information is provided to the FDA
and investigators
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Sponsor

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Investigator
 An investigator is an individual under whose
immediate direction the study drug is
administered or dispensed. If a team is
involved, the leader is the investigator; other
team members are sub-investigators
(21 CFR 312(b), 312.60)
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Definitions


Sponsor-Investigator
 A sponsor-investigator is an individual
who both initiates and conducts a study
and under whose immediate direction the
study drug is administered or dispensed.
This person must follow the requirements
pertaining to a sponsor and those
pertaining to an investigator
(21 CFR 312(b))
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Definitions

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IND Requirements

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1. Commercial IND
2. Emergency use IND
3. Treatment IND
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TYPE OF IND

 To focus FDA’s attention during early phase
of clinical research on assuring the safety of
human test subjects.
 To provide sponsors with a greater measure
of flexibility in conducting Phase 1 trials.
 To facilitate consultation between FDA &
sponsors, especially after there is an
indication that the new drug is safe and
efficacious in humans.
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Objective

 Cover Sheet (Form FDA 1571)
 Table of Contents
 Introductory Statement & General investigational
plan
 Investigator’s Brochure
 Protocols
 Chemistry, Manufacturing & Control Information
 Previous Human Experience with the Investigational
Drug
 Additional Information
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IND Content Requirements
21 CFR 312.23


 The form is provided for basic information
like name of drug, submission date, sponsor
identification, phase of proposed clinical
investigation, sponsor commitments,
identification of clinical monitor and safety
evaluator, information regarding transfer of
responsibilities to a contract research
organization.
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Cover Sheet (form FDA
1571)


Drug Name®
IND table of contents
Item title volume/page
Introductory statement &
general investigational plan…
(i) Introductory statement….
(ii) summary of previous human experience
with drug…….
(iii) If the drug has been withdrawn from
Investigation/Marketing……
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Table of Contents

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iv)iv) General Investigational Plan…..General Investigational Plan…..
5 Investigator’s Brochure…….5 Investigator’s Brochure…….
6 Protocol……..6 Protocol……..
7 Chemistry, Manufacturing & Control7 Chemistry, Manufacturing & Control
Information…Information…
(a) Drug substance…………(a) Drug substance…………
(b) Drug Product…………….(b) Drug Product…………….
(c) Placebo (if applicable)…(c) Placebo (if applicable)…
(d) Labeling…………………….(d) Labeling…………………….
(e) Environmental Analysis ….(e) Environmental Analysis ….
8 Pharmacology & Toxicology8 Pharmacology & Toxicology
Information…….Information…….


9)Previous Human Experience with the
Investigational Drug…….
(i) Summary of Previous Human Experience….
(ii) If the drug is a combination of drug
previously investigated/marketed…….
(iii) If the drug has been marketed outside the
United States……
10 Additional Information (as applicable for
radioactive drugs or drugs with dependence or
abuse potential)….
03/22/15 19www.PharmInfopedia.com


It consists of four subsections:
1st
subsection: (introductory statement)
 Name of drug
 P’cological Class
 Structural formula
 Route of administration
 Broad objectives
 Planned duration of the proposed clinical
investigation03/22/15 20
Introductory Statement & General
Investigational Plan:


2nd
subsection:
 Brief summary of any previous human
experience with the drug, including
investigational or marketing experience in other
countries
3rd
subsection:
 It is a statement as to whether or not the drug
has been withdrawn from investigation or
marketing in any country for any reason of
safety or efficacy


4th
subsection:
 Brief description of overall investigational plan for
drug during the following year like: Indications to be
studied, kinds of clinical trials to be conducted in
first year


 Sponsor must provide to all clinical
investigators, not required for sponsor
investigators (21 CFR 312.55). It must
include:
 Brief product description
 Pharm/tox summaries
 Previous human experience
 Description of anticipated risk and any special
monitoring needs
 Updates as appropriate03/22/15 23
Investigator’s Brochure (IB)

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Drug Name®
Investigator's Brochure
Table of contents
Page
Introduction……………………..
Chemistry……………………….
Physical Properties……
How Supplied…………….
Pharmacology………………….
Specific Effect Studies…
General Studies………….


Toxicology………………………..
Acute Toxicity…………….
Multidose Toxicity……….
Special Toxicity Studies………
Reproductive Studies……
Mutagenicity Studies…….
Pharmacokinetics………………
Preclinical…………………….
Clinical………………………….
Clinical Trial……………………….
Phase 1…………………………
Phase 2/3… ………………….


Safety/Efficacy Overview
Safety…………………………..
Efficacy………………………..
Possible Risks and Side Effects…
References………………………….


 Phase 1 protocol provides an outline of
investigation by specifying information
such as estimated number of test
subjects, inclusion/exclusion criteria and
dosing plan
 Phase 2 and Phase 3 protocols are detailed,
describing all aspects of the studies, such
that any deviation in a design if required, it
can be established in the protocol from
the beginning.
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5 Protocols


All the protocols are required to contain the
following elements:
 Statement of the objectives and purpose of the study
 Patient inclusion/exclusion criteria
 Estimate of number of patients to be studied
 Description of study design
 Dosing information including planned maximum
dosage and duration of individual patient exposure to
the Drug
 Description of the observations and measurements
planned to fulfill the study objectives


 Emphasis in Phase I is on identification and
control of raw materials and new drug substance,
including information on any placebo as well
 Even for Phase I, need enough information to
assess safety
 Extent of expected information increases as drug
development proceeds
 Throughout product development, good
documentation of all manufacturing and testing
steps is essential
 Deficiencies in CMC information can result in
clinical hold03/22/15 30
CMC Information


 Previous human experience needs to be included (if
applicable)
 Additional information such as pre-IND meeting
minutes or critical references should be included as
well
 Serial numbering of pages of an IND is required (21
CFR 312.23(11)(e)) as this facilitates reference if the
FDA has questions
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Other IND Items


21 CFR 312.30
 A new protocol
 Safety or design related changes to an
existing protocol
 New investigator (notification is required
within 30 days of being added)
 These should be submitted to the FDA prior
to implementation
 IRB approval is needed prior to
implementation03/22/15 33
IND Protocol
Amendments


21 CFR 312.31
Information amendments advise the FDA of:
 New tox, CMC or other technical information
 Notice of discontinuance of a clinical study
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IND Information
Amendments


 If a sponsor notify any unexpected fatal / life
threatening experience associated with the use of the
drug requires to notify the FDA by telephone no
later than 3 working days after receipt of the
information, followed by a written report within 10
days.
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IND Safety Reports:


21 CFR 312.33
 To be submitted within 60 days of the
anniversary of “in effect” date
 Include enrollment, demographic and
conduct status information for each study
 Adverse event summaries (safety reports,
deaths, dropouts)
 Drug action information
 Preclinical study status information03/22/15 36
Annual Reports


 CMC change information
 Revised/updated investigator brochure with
revisions described
 Foreign marketing experience
 Outstanding business with the FDA
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Annual Reports (cont’d)


It is option of a sponsor to withdraw an IND at any
time without prejudice.
On withdrawn, sponsor must notify the FDA.
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Withdrawal of an IND


Two major outcomes from the IND discussion
are:
 30 days after an IND is submitted to the FDA, if the
sponsor has not heard anything from the FDA it
can be assumed that the drug is not on a clinical
hold and clinical trials may be started
 The Investigator’s Brochure, which will be used
during that important first clinical study and in
every clinical study thereafter, acts as the approved
labeling for the drug while it is under an IND
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Conclusions


1.www.fda.gov/cder/about/history/time1.htm
2.Remington the science and practice of pharmacy,
20th edition, Lippincott,Williams & Wilkins, page
no: 930-943
3. New Drug Approval Process: second Edition,
Revised and Expanded, edited by Richard A.
Guarino page no: 39-64, 243-263
4.www.fda.gov/cder/handbook/indbox.htm
5.www.fda.gov/cder/handbook/ndabox.htm
6.www.fda.gov
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List of references

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Investigational new drug application

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