Transcript Investigational New Drug

Investigational New Drug
Application
(IND)
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CRC Orientation Prerequisite
January 2008
Definitions
 Investigational New Drug is a new drug or biologic used in a
clinical investigation
 Investigational New Drug (IND) application is a request to FDA
for authorization to administer an investigational drug or biologic to
humans ( synonymous with a “Notice of Claimed Investigational
Exemption for a New Drug”)
 Sponsor is an individual, company, academic institution, or other
organization that takes responsibility for and initiates a clinical
investigation
 Investigator is an individual under whose immediate direction a
drug is administered or dispensed
 Sponsor-Investigator is means an individual who both initiates and
conducts an investigation. The term does not include any person
other than an individual.
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January, 2008
What is an IND?
 After preclinical studies provide sufficient data to
warrant study in humans, an IND is submitted to
the FDA (Food and Drug Administration)
 The IND is a request for authorization from the
FDA to administer an investigational drug or
biological product to humans. Such authorization
must be secured prior to interstate shipment and
administration of any new drug or biological
product that is not an approved drug or biologic
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January, 2008
IND Regulations
 The regulations in 21 CFR 312 cover procedures
and requirements for Investigational New Drug
Applications (INDs)
 These regulations also define the roles and
responsibilities of FDA reviewers, IND sponsors,
and clinical investigators
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January, 2008
FDA’s primary objectives in reviewing
an IND
 In all phases of the investigation, to assure
the safety and rights of subjects
 In Phase 2 and 3 to help assure the scientific
quality for evaluation of drug’s safety and
effectiveness
21 CFR 312.22
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January, 2008
Who Submits INDs?
 A sponsor (e.g. pharmaceutical or
biological company)
 A sponsor-investigator (e.g. investigator
initiated IND)
 Other entities that want to conduct clinical
research with an investigational product
(e.g. Foundations, Government agencies)
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January, 2008
IND Content Requirements
21 CFR 312.23
Format pertains to all sponsors and sponsor
sponsor-investigators
 Cover Sheet (and Form FDA 1571):
http://www.fda.gov/opacom/morechoices/fdaforms/1571es.pdf
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Table of Contents
Introductory Statement and General Investigational Plan
Investigator Investigator’s Brochure (or Plan)
Clinical Protocol
Chemistry, Manufacturing and Control (CMC) Information
Pharmacology and Toxicology Information
Previous Human Experience
Additional Information
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January, 2008
IND Filing Process
 FDA is required by regulation to respond within 30
days of the filing of an initial IND
 If no issues are identified, the IND is considered to
be in effect (“approved”) and the sponsor may start
the study
 If issues cannot be resolved within this 30 day
period, the FDA can place the study on clinical
hold
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January, 2008
FDA Review
FDA Review Process Includes:
Safety
Medical/clinical
Chemistry
Pharmacology/ Toxicology
Statistical
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January, 2008
IND Categories
 Commercial
Ultimate goal is to obtain marketing approval and is
typically 5+ volumes for a Phase 1 IND
Example: Submission by a Pharmaceutical
Company
 Research (non-commercial)
Primarily research-driven, not marketing approval
IND can be a single volume If preclinical and
manufacturing information can be cross-referenced
to a prior IND
Example: IND submission by Duke Physician
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January, 2008
Other Types of INDs
 Emergency Use
Used only with a life-threatening situation that does not allow
time for submission and review of an IND
The IND must be submitted as soon as possible
 Exploratory IND
Study is conducted early in Phase 1
Involves limited human exposure (non-pharmacologically
active dose)
Has no therapeutic or diagnostic intent
Requires less preclinical data to support study
 Treatment IND
Used to make promising new drugs available to desperately
ill patients as early in the drug development process as
possible. These patients are not eligible to be in the
definitive clinical trials, which must be well underway, if not
almost finished.
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January, 2008
When is a study exempt from an IND?
 All six criteria must be met for a study to be
considered exempt from requiring an IND
(1) If the study is not designed to support approval of a new
indication or a change in label
(2) If the study is not intended to support a significant change
in the advertising for the product
(3) If the study does not involve a route of administration,
dosage level or patient population that significantly
increases the risks (or decreases the acceptability of the
risks) associated with the use of the drug
(4) The study is conducted in compliance with the IRB and
informed consent regulations
(5) The study is conducted in compliance with regulations
regarding promotion and charging for investigational drug
(6) It does not intend to invoke 21 CFR 50.24 (Exception from
Informed Consent requirements for emergency research)
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January, 2008
IND Holder Responsibilities
 If an investigator submits an IND, they are
responsible for following the regulations for
both a Sponsor and an Investigator (SponsorInvestigator)
21 CFR 312.3(b)
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January, 2008
Sponsor Responsibilities
(21 CFR 312.50-59)
 Select qualified investigators
 Ensure that the investigation is conducted in
accordance with the protocols in the IND
 Ensure proper monitoring of the investigation
 Maintain an effective IND
 Promptly inform FDA and all investigators of
significant new adverse events
 Maintain adequate records, reporting and
monitoring of the investigation to include product
accountability
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January, 2008
Investigator Responsibilities
(21 CFR 312.60-68)
 Commitment to Item 9 on Form
FDA 1572
http://www.fda.gov/opacom/morech
oices/fdaforms/FDA-1572_508.pdf
 Agrees to personally supervise the
investigation
 Ensures investigation is conducted
according to the investigational plan
and applicable regulations
 Protects the rights, safety and
welfare of study subjects, and
obtain their informed consent
 Controls investigation drugs
 Reports to the sponsor adverse
experiences that occur in the
course of the investigation
 Ensures an IRB will review and
approve of the clinical investigation.
Also commits to promptly providing
the IRB with information on
changes and problems involving
risks to human subjects
 Prepares and maintains adequate
and accurate case histories that
record all observations and other
data pertinent to the investigation
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January, 2008
IND Amendments
 IND is a living document which may be in effect
for years or decades
 INDs are updated via amendments:
Protocol amendments (21 CFR 312.30)
Information amendments (21 CFR 312.31)
Safety reports (21 CFR 312.32)
Annual reports (21 CFR 312.33)
Response to FDA request for information
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January, 2008
Protocol Amendments
 A new protocol
 Changes to an existing protocol
 New investigator or updated Form 1572
 Protocol amendments must be submitted to FDA
prior to implementation
 IRB approval is required prior to implementation
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January, 2008
Information Amendments
 Clinical data (not protocol related)
 Pharmacology or toxicology data
 Chemistry Manufacturing and Control (CMC)
information
 Notice of discontinuance of a clinical study
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January, 2008
IND Safety Reports
 The investigator is required to promptly inform the sponsor of any
adverse effect that may reasonably be regarded as caused by, or
probably caused by the drug (21 CFR 312.64[b]).
 The sponsor shall notify the FDA and all participating investigators
in a written IND Safety Report of any adverse experience
associated with the use of the drug that is both serious and
unexpected and any laboratory tests that suggests a significant
risk for human subjects (21 CFR 312.32)
A written IND safety report must be submitted within 15
calendar days of receipt of the information to FDA and all
investigators
For an unexpected fatal or life-threatening experience, the
sponsor must inform FDA no later than 7 days of receipt of the
information
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January, 2008
Annual Reports
 Must be submitted within 60 days of the
anniversary date that the IND went into effect.
 Information that should be provided includes:
Brief summary of each study in progress under the
IND
Summary of information obtained during previous
year (most frequent AE’s by body system, IND
safety reports, deaths, dropouts, list of preclinical
studies, CMC or microbiological changes)
Updated general investigational plan for coming year
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January, 2008
Summary of the IND Process and
Interaction with FDA
Basic
Research
Industry – FDA
Interactions
During
Development
Prototype
Design or
Discovery
Clinical Development
Preclinical
Development
Phase 1
Pre-IND Meeting
Phase 2 Phase 3
End of
Phase
2a Meeting
Initial
IND
Submissions
End of Phase 2
Meeting
Ongoing
Submission
Safety Update
BLA or NDA
Application
Submission
Pre-Biologic License Application (BLA) or
New Drug Application (NDA) Meeting
IND Review Phase
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January, 2008
FDA Filing/
Approval &
Launch
Preparation
Application
Review Phase