Investigational New Drug Application (INDA)

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Investigational New Drug Application (INDA)
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LIST OF CONTENTS..

• What is INDA ?
• Types of INDAs
• Objectives of INDAs
• Format Contents of an INDA
• IND Safety reports
• IND Annual Reports
• IND Review Process
• Withdrawal of an IND
• Inactive Status
• References

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• What is INDA ?

(Fig. Flow chart illustrating the various steps
in preclinical and clinical development of
pharmaceutical Products)
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• INDA is a vehicle through which a sponsor
  advances to the next stage of drug product
  development known as clinical trials (human
  trials) .
• It includes data and information in three broad
  areas
• Animal Pharmacology and Toxicology Studies
• Manufacturing Information
• Clinical Protocols and Investigator Information
• The regulations in 21 CFR 312 cover procedures
  and requirements for Investigational New Drug
  Applications (INDAs) .
• These regulations define the roles and
  responsibilities of FDA reviewers, IND sponsors,
  and clinical investigators .

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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)
• 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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• 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) .
• An investigator is responsible for
• Ensuring the study is conducted according to the
  plan
• Protecting the rights, safety and welfare of
  subjects, and
• Control of drug under investigation

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• 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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Types of INDs

1. Commercial INDs
2. Emergency use INDs
3. Treatment INDs

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Objectives of INDA

• To focus FDAs 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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Format Contents of an INDA(21 CFR 312.23)

• Cover Sheet (Form FDA 1571)
• Table of Contents
• Introductory Statement General investigational
  plan
• Investigators Brochure
• Protocols
• Chemistry, Manufacturing Control Information
• Previous Human Experience with the
  Investigational Drug
• Additional Information

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Cover Sheet (Form FDA 1571)

• 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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Table of Contents

• Drug Name
• IND table of contents
• Item Title
  volume/page
• 3 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
• iv) General Investigational Plan..

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5 Investigators Brochure. 6 Protocol.. 7
Chemistry, Manufacturing Control Information
(a) Drug substance (b) Drug
Product. (c) Placebo (if applicable)
(d) Labeling. (e) Environmental
Analysis . 8 Pharmacology Toxicology
Information.
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• 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).

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Introductory Statement General Investigational
Plan

• It consists of four subsections
• 1st subsection (Introductory statement)
• Name of drug
• Pcological Class
• Structural formula
• Route of administration
• Broad objectives
• Planned duration of the proposed clinical
  investigation

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• 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 .

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• 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.

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Investigators Brochure (IB)

• Sponsor must provide to all clinical
  investigators, not required for sponsor
  investigators (21 CFR 312.55).
• It must include
• Brief product description
• Pharmacology/toxicology summaries
• Previous human experience
• Description of anticipated risk and any special
  monitoring needs
• Updates as appropriate

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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.

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

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• Safety/Efficacy Overview
• Safety..
• Efficacy..
• Possible Risks and Side Effects
• References.

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Protocols

• 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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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

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Chemistry, Manufacturing Control Information

• Drug Substance
• Physical, chemical or biological characteristics
  of the drug substance, along with the name and
  address of the manufacturer
• Description of the general method of preparation,
  identification of the analytical methods and
  acceptable limits used to assure the identity,
  purity and strength of the drug substance
• Stability data must be sufficient to support the
  stability of drug substance throughout the
  preclinical and proposed clinical studies

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• Drug Product
• Qualitative Quantitative compositions
• Manufacturing facility, manufacturing and
  packaging procedure, identification of analytical
  methods, acceptable limits used to assure
  identity, purity, and strength of components and
  finished products
• Stability data to support duration of proposed
  clinical studies.
• Labeling
• A copy of all labels and labeling to be provided
  to each clinical investigations must be
  submitted.
• Environmental Analysis
• Identification and quantities of any chemical
  substances emitted during the manufacture of the
  product, use of resources and energy, etc.

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• Previous Human Experiences with the
  Investigational Drug
• Such findings if available must be submitted
  whether drug is marketed in U.S. or other foreign
  country.
• Additional Information
• Any information that sponsor believes will aid in
  the evaluation of the application.
• IND Amendments
• Protocol Amendments
• Information Amendments

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IND Safety Reports

• 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 Annual 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 information

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IND Review Process
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Withdrawal of an IND

• 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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Inactive Status

• On sponsors request FDA may place an IND on
  inactive status if no subjects have entered
  clinical studies for at least two years or if the
  IND has been on clinical hold for at least one
  year.
• After remaining on inactive status for five
  years, the FDA may terminate an IND.

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List of References

• 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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Thanks to All