Investigational New Drug Application The IND

1
Investigational New Drug Application ( The IND)

• Laws governing the IND
• Section 505(a) of Food Drug Cosmetic Act
• To obtain approval of New Drug Application (NDA)
• Drug must be distributed for clinical safety
  studies in humans
• New drugs CANNOT be shipped for clinical use in
  humans without an FDA reviewed application
• (from regsource.com obtain 21 CFR 50, 56, 312)

2
Investigational New Drug The IND Application

• Roles of an IND Application
• Formal, legal request for exemption from Federal
  statutes
• Section 505(a) of FDC Act
• Bars the transport of unapproved drugs from
  interstate commerce without an approved marketing
  application.
• Alert FDA
• Intent to conduct clinical studies with an
  investigational drug.
• Detailed description of pharmacological activity
• Provide justification for commercial development.

3
Investigational New Drug The IND Application

• Requirements of 505(i) of FDC Act
• Report filed to justify proposed testing (IND)
• Signed agreement from investigators (FORM FDA
  1572)
• Commitment to supervise patients and clinical
  study
• Adequate records must be maintained to evaluate
  safety and efficacy
• Informed consent must be obtained to ensure
  adequate protection of the research subjects
  rights

4
21 CFR 312.40Use of an Investigational Drug

• General Requirements
• Sponsor must file notice of exemption with FDA
  (IND)
• Exemption must be in effect
• IND goes into effect 30 days after FDA receives
  application unless notified by FDA of clinical
  hold (21 CFR 312.42) (see chapt. 4)
• FDA provides written notification to the Sponsor
  of date IND was received
• Each investigator must comply with Informed
  Consent and IRB regulations

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21 CFR 312.22General Principles of the IND
Application

• Federal Regulations define
• FDAs Primary objective when reviewing an IND
• Assurance
• Safety and rights of subjects
• Quality of scientific evaluation of drugs is
  adequate
• FDAs role in the application review
• Administrative Silence
• Clinical Hold
• IND format (21 CFR 312.23) (see Form FDA 1571)
• Foster efficient review process
• See slides 15

6
Applicability of the IND21 CFR 312.2

• IND is a requirement for all persons or firms
• seeking to ship unapproved drugs over state
• lines for the use in clinical investigations
• Exclusions
• Data is not intended to be used to report to the
  FDA in support of a new indication/ change in
  drug labeling.
• Not intended to make significant changes to
  advertising for prescription drug.
• No change in route of administration, dosage
  level, patient population.
• Drugs used solely for in vitro or used on
  research animals.

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Types of INDs

• Commercial Use IND
• Investigator IND
• Emergency Use IND
• Treatment IND
• Compassionate Use IND
• Fast track designation
• Screening IND

8
Commercial Use IND

• Ultimate goal is to achieve marketing approval
  for new product
• Pharmaceutical companies

9
Investigator/Sponsor IND

• IND submitted by physician who initiates and
  conducts an investigation on previously studied
  drugs. Same obligations as pharma. Company!
• Proposed study for
• Unapproved drug
• Approved product for
• New indication
• New patient population
• Motivation is not necessarily commercial in
  nature
• Treatment of patients or obtain data to publish
  research paper

10
Emergency Use IND21 CFR 312.36

• Procedure through which the FDA can authorize
  shipment of unapproved, experimental drug for
  desperate medical situation
• Time does not allow for for traditional
  submission of an IND
• No existing approved protocol
• Subject does not meet criteria of existing
  protocol
• Emergency uses are specified in advance

11
Emergency Use IND

• Reserved for life-threatening situations
• No standard acceptable treatment is available
• Insufficient time to obtain IRB approval
• Secure approval within 5 days after use
• Informed consent obtained if possible

12
Treatment IND

• Experimental drugs showing promise in clinical
  testing-safety and efficacy
• After completion of Phase I and II
• Used for the treatment of serious or life
  threatening conditions
• No alternate treatments available
• AIDS, Cancer
• Made available while final clinical testing is
  completed and reviewed by the FDA
• Reduce reluctance of people to participate in
  expanded drug access programs

13
Compassionate Use IND

• Investigational product made available to
  subjects ineligible for Phase II and III clinical
  studies.
• Determined on case-by-case basis
• FDA
• Sponsor
• Example
• Alternate indication
• Breast cancer drug to leukemia patient
• Limited protocol and data collection requirements
• Small group of patients
• Not used in support of NDA

14
Fast Track Designation

• Designated for drug therapy that addresses unmet
  medical needs
• Sponsor requested
• Serious or life threatening conditions
• Created under FDA Modernization Act of 1997
• Special disease state populations
• AIDS
• Cancer

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Content and Format of the IND21 CFR 312.23

• All available information impacting on SAFETY!
• Animal studies
• Pharmacology
• Toxicology
• Previous clinical experience
• Foreign and domestic sources
• Scientific literature

16
Content and Format of the IND21 CFR 312.23

• Test article information and proposed dosage form
• Chemical structure
• Manufacturing and purification techniques
• Analytical testing methods
• Physical characteristics
• Stability

17
Content and Format of the IND21 CFR 312.23

• Overall plan of study for next year (minimum)
• Proposed protocols with justification
• Patient Inclusion Exclusion criteria
• Method of patient selection to prevent bias
• Identification qualifications of investigators
  sub-investigators
• Assurances of investigator supervision
• Assurances sponsor monitor
• Identification of key responsible individuals

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IND Content and Format Requirements

• Form FDA 1571
• Table of contents
• Introductory statement
• General investigational plan
• Investigators brochure
• Clinical protocols
• Chemistry, manufacturing and control data
• Pharmacology and toxicology data
• Previous human experience

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Cover Sheet FDA Form 1571 Basic Functions

• Establishment of the nature of the investigation
• Initial submission
• Amendment
• Agreement to comply with regulations
• Refraining to initiate clinical studies until
  IND is in effect

• Identify
• Sponsor
• Investigational drug
• Individuals responsible for monitoring of
  clinical trial and safety related trial
  information
• Phases covered by the proceeding report
• Responsibilities transferred to CRO

20
Introductory Statement

• Description of the investigational drug
• All active ingredients
• Drugs pharmacological classification
• Structural formula
• Route of administration

21
Introductory Statement

• Goals of the proposed clinical investigations.
• Summary of previous human experience.
• Formulation of the dosage forms.
• Objectives and planned duration of proposed
  clinical investigation.

22
Investigational Plan

• Description of clinical studies planned for the
  experimental drug
• Minimum 1 year
• Scale of study
• Rationale for the drug or research study
• Indications to be studied
• Types of trials to be initiated
• Number of study subjects
• Risks

23
Investigators Brochure21 CFR 312.23(5)(i)-(v)

• Structural formula of drug
• Summary of pharmacological, toxicological,
  pharmacokinetic effects in animals
• Safety and effectiveness
• Reprints of related articles

• Purpose of study
• Dose/dose frequency
• Method of administration
• Monitoring procedures
• Risk benefit assessment

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Clinical ProtocolsSee Chapter 3

• FDA reviews protocols to
• Ensure subjects not exposed to any unnecessary
  risks
• Phase 2 and 3 studies designs are adequate to
  provide the type and amount of information
• Demonstrate effectiveness and safety
• Considered the most important part of the IND
• IND review of protocols is intended to evaluate
  safety of the drug
• Estimate number of subjects
• Describe safety
• Exclusion and Inclusion
• Describe dosing regimen
• (You are expected to fully understand the design
  and development of a clinical protocol)

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Chemistry, Manufacturing and Control Data (CMC)

• Determine the adequacy of methods used to
  manufacture and assay investigational compound
• Safety concerns
• Describe drug substance
• Identify manufacturer
• Method of preparation
• Reagent and solvents
• Acceptable limits and analytical methods to
  ensure quality and purity of drug

26
Pharmacology and Toxicology Data

• Pharmacology and Drug Disposition
• Integrated Toxicology Summary

27
Previous Human Experience

• Marketed (foreign) or previously tested in humans
  
• Drug
• Active ingredients
• Must provide specific information relevant to
  FDAs evaluation

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Submission of the IND

• Sponsor must submit
• Original
• Two copies
• Translation required
• Accurate and completed English translation for
  any information written in a foreign language
• Must submit original foreign language document on
  which translation was based

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Maintaining/Updating the IND

• Annual Reports
• 21 CFR 312.33
• Protocol Amendments
• 21 CFR 312.30
• IND Safety Reports
• 21 CFR 312.32
• Information Amendments
• 21 CFR 312.31

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Annual IND Report21 CFR 312.33

• Status of each clinical study
• Summary of data obtained in last year
• List of research subjects who have
• Died
• Dropped out due to adverse reactions
• List of animal studies and findings obtained in
  last year
• General investigational plan for upcoming year

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Protocol Amendments21 CFR 312.30

• Protocol Amendments are to be identified in one
  of three ways
• Protocol Amendment - New Protocol
• Protocol Amendment - Change in Protocol
• Protocol Amendment - New Investigator
• Must be submitted to FDA prior to implementation

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Protocol Amendments21 CFR 312.30

• Protocol Amendments are required when
• Modifying Phase 1 protocol
• Significantly affects safety of clinical subjects
• Modifying Phase 2 or 3 protocol
• Significantly affects safety of research subjects
• Scope of the investigation
• Scientific quality of the study
• Changes to existing protocols must include
• Description of change
• Reference original protocol

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Examples of Protocol Changes Requiring Amendments

• Addition of new test or procedure intended to
• Improve monitoring
• Reduce risk of side effects or adverse events
• Elimination of
• Immediate hazard to subjects
• Test intended to monitor safety
• (Do not start without IRB approval)

• Increase in
• Drug dosage
• duration of exposure
• Study subjects
• Significant change in protocol design
• Addition/deletion of control or study group
• Addition of an investigator

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IND Safety Reports21 CFR 312.32

• Function to inform FDA of any adverse experience
  (AE)
• Associated with the use of the product
• Both serious and unexpected
• Ensure timely communication

35
IND Safety ReportsSponsors Responsibilities

• Promptly review all information
• Relevant to the safety of the drug
• Obtained from any source, foreign or domestic
• Including information derived from
• Clinical or epidemiological investigation
• Animal investigation
• Commercial marketing experience
• Scientific literature
• Unpublished scientific literature
• Foreign regulatory authorities

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IND Safety ReportsTerminology

• Serious Adverse Drug Experience
• Unexpected Adverse Drug Experience
• Associated with the Use of the Drug
• Life-Threatening Adverse Drug Experience
• Disability

37
IND Safety ReportsTerminology

• Serious Adverse Drug Experience
• Results in one the following outcomes
• Death
• Life-threatening adverse drug experience
• Inpatient hospitalization
• Prolongation of existing hospitalization
• Persistent or significant disability
• Congenital anomaly/birth defect
• Require medical intervention to prevent one of
  the outcomes listed above

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IND Safety ReportsTerminology

• Unexpected Adverse Drug Experience
• Any adverse experience, in which the specificity
  and severity is not consistent with the
  Investigators Brochure

39
IND Safety ReportsTerminology

• Associated with the Use of the Drug
• Reasonable possibility that the experience may
  have been caused by the drug

40
IND Safety ReportsTerminology

• Life -Threatening Adverse Drug Experience
• Places the patient at immediate risk of death
  from the reaction that occurred

41
IND Safety ReportsTerminology

• Disability
• Substantial disruption of persons ability to
  conduct normal life functions
• Must be persistent and significant
• Not intended to include minor medical conditions
• Headache
• Nausea
• Vomiting
• Diarrhea
• Accidental trauma

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Information Amendments21 CFR 312.31

• Report information to FDA that
• Immediately critical to disseminate information
• Would not be included in Annual or Safety Reports
  
• Represents majority of IND Amendments
• New animal data (pharmacology/toxicology)
• Changes or additions to chemistry, manufacturing
  and controls section
• Discontinued trials
• Responses to CDER requests
• Changes in IND contact individuals