Investigational New Drug Application (INDA)

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Investigational New Drug Application (INDA)
PRESENTED BY- Dillip Kumar Jena
Dept of pharmaceutics pharmaceutical
Technology LMCP
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WHAT I WILL TELL

• INTRODUCTION
• REGULATORY ASPECT
• TYPE OF IND
• REQUIERMENT IND
• CONTENT OF IND
• IND AMENDMENT
• ANNUAL REPORT OF IND
• CONCLUSION

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• What is INDA

General introduction

• this data and information is generated and
  gathered from three broad areas
• Animal Pcology Toxicology studies
• Manufacturing information
• Clinical Protocols Investigator Information

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Regulation

• 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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Definitions

• 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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Sponsor

• 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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Definitions

• 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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Investigator

• 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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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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IND Requirements
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IND Requirements (contd)

• For a lawfully marketed product, no IND
  submission is required if three specific
  conditions apply (21 CFR 312.2)
• The study is not intended to support a new
  indication or labeling change
• The study does not intend to support a change in
  advertising
• The study does not involve a route, dosage or
  patient population, etc. that increases risk

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NOTE!

• The FDA may be aware of other studies that may
  affect evaluation of potential risk, and
• the FDA is subject to confidentiality
  requirements and by law can not share this
  specific information with others

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TYPE OF IND

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

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Objective

• 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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IND Content Requirements21 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)

• 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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Table of Contents

• 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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iv) General Investigational Plan.. 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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• 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).

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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
• Pharm/tox 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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Introductory Content Elements

• Cover Sheet (Form FDA 1571)
• Table of Contents
• Introductory Statement (description of product,
  formulation, route, broad study objectives,
  relevant previous use, foreign experience)
• General Investigational Plan (rationale,
  indication, general approach, anticipated studies
  including number of subjects and possible risks)

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5 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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CMC Information

• 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 hold

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Pharm/Tox Information

• Animal studies may be conducted to obtain proof
  of concept or tox information
• Studies should support proposed clinical dose and
  regimen
• Best to get CBER concurrence on pivotal tox
  protocols prior to initiation
• Need to submit complete study reports for tox
  studies, including summary and individual animal
  data

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Other IND Items

• 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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IND Protocol Amendments

• 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 implementation

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IND Information 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 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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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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Annual Reports (contd)

• CMC change information
• Revised/updated investigator brochure with
  revisions described
• Foreign marketing experience
• Outstanding business with the FDA

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Annual Reporting of Adverse Events

• RECOMMENDATIONS
• For solicited events tabulate by study, study
  group and severity
• For unsolicited events use a line listing by
  study
• SAEs should be highlighted and discussed
• Include numerators and denominators
• Include cumulative cross-study, multi-year
  summaries
• Include all events regardless of attribution of
  relatedness to study drug

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Specific Responsibilities of Sponsors

• Selecting qualified investigators and monitors
  (21 CFR 312.53)
• Obtaining investigator information (signed Form
  FDA 1572 and CV)
• Controlling shipment of drug only to
  participating investigators
• Obtaining clinical protocol information
• Obtaining financial disclosure information
• Providing each investigator an investigator
  brochure (21 CFR 312.55)
• Informing investigators of new safety
  observations (see 21 CFR 312.32 on IND safety
  reports)

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Specific Responsibilities of Sponsors

• Review ongoing investigations (21 CFR 312.56)
• Monitor study progress for compliance with
  protocol
• Dealing with noncompliant investigators
• Review and report to FDA safety and effectiveness
  data (annual reports and IND safety reports)

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Specific Responsibilities of Sponsors

• Maintenance of adequate records (21 CFR 312.57)
  including
• Tracking of drug shipment and information
• Recording financial interest of investigators
• Keeping records for 2 years post approval or post
  last IND drug shipment
• Retention of reserve samples and standards for
  certain tests
• Providing FDA with records upon request (21 CFR
  312.58)
• Proper disposition of unused investigational drug
  (21 CFR 312.59)

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Specific Responsibilities of Investigators

• Control administration of investigational drug
  (21 CFR 312.61)
• Provide qualification and study conduct
  information to sponsor
• Following the protocol (commitment to this
  required per Form FDA 1572)
• Maintenance of records (21 CFR 312.62) including
• Drug disposition
• Case histories (CRFs, ICFs, medical records)
• Keeping records for 2 years post approval or post
  study discontinuation

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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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Conclusions

• 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 Investigators 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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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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Thank You
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Specific Responsibilities of Investigators

• Reports to sponsor (21 CFR 312.64)
• Providing progress reports for IND annual report
• Promptly reporting safety concerns
• Provision of final report after study completion
• Providing financial disclosure information
• Assuring IRB review (21 CFR 312.66)
• Providing FDA with records upon request (21 CFR
  312.68)