1CRC Orientation Prerequisite
January 2008
Investigational New Drug Application
(IND)
2January, 2008
DefinitionsDefinitions 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.
3January, 2008
What is an IND?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
4January, 2008
IND RegulationsIND 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
5January, 2008
FDA’s primary objectives in reviewing FDA’s primary objectives in reviewing an IND 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
6January, 2008
Who Submits INDs?Who Submits INDs?
A sponsor (e.g. pharmaceutical or A sponsor (e.g. pharmaceutical or biological company)biological company)
A sponsor-investigator (e.g. investigator A sponsor-investigator (e.g. investigator initiated IND)initiated IND)
Other entities that want to conduct clinical Other entities that want to conduct clinical research with an investigational product research with an investigational product (e.g. Foundations, Government agencies)(e.g. Foundations, Government agencies)
7January, 2008
IND Content Requirements21 CFR 312.23
Cover Sheet (and Form FDA 1571): http://www.fda.gov/opacom/morechoices/fdaforms/1571es.pdf
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
Format pertains to all sponsors and sponsor sponsor-investigators
8January, 2008
IND Filing ProcessIND 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
9January, 2008
FDA ReviewFDA Review
FDA Review Process Includes: FDA Review Process Includes:
SafetySafety
Medical/clinicalMedical/clinical
ChemistryChemistry
Pharmacology/ ToxicologyPharmacology/ Toxicology
StatisticalStatistical
10January, 2008
IND CategoriesIND 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
11January, 2008
Other Types of INDsOther Types of INDs
Emergency Use Used only with a life-threatening situation that does not allow time for submission and review of an INDThe IND must be submitted as soon as possible
Exploratory INDStudy is conducted early in Phase 1 Involves limited human exposure (non-pharmacologically active dose)Has no therapeutic or diagnostic intentRequires less preclinical data to support study
Treatment INDUsed 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.
12January, 2008
When is a study exempt from an IND? 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) )
13January, 2008
IND Holder ResponsibilitiesIND Holder Responsibilities
If an investigator submits an IND, they are If an investigator submits an IND, they are responsible for following the regulations for responsible for following the regulations for both a Sponsor and an Investigator (Sponsor-both a Sponsor and an Investigator (Sponsor-Investigator)Investigator)
21 CFR 312.3(b) 21 CFR 312.3(b)
14January, 2008
Sponsor ResponsibilitiesSponsor 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
15January, 2008
Investigator ResponsibilitiesInvestigator Responsibilities(21 CFR 312.60-68)(21 CFR 312.60-68)
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
Commitment to Item 9 on Form FDA 1572 http://www.fda.gov/opacom/morechoices/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
16January, 2008
IND AmendmentsIND 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
17January, 2008
Protocol AmendmentsProtocol 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
18January, 2008
Information AmendmentsInformation Amendments
Clinical data (not protocol related)
Pharmacology or toxicology data
Chemistry Manufacturing and Control (CMC) information
Notice of discontinuance of a clinical study
19January, 2008
IND Safety ReportsIND 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
20January, 2008
Annual ReportsAnnual 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
21January, 2008
Summary of the IND Process and Summary of the IND Process and Interaction with FDAInteraction with FDA
Basic Research
Basic Research
PrototypeDesign or Discovery
PrototypeDesign or Discovery
FDA Filing/Approval &
LaunchPreparation
FDA Filing/Approval &
LaunchPreparation
Preclinical Development Preclinical Development
Clinical Development
Phase 1 Phase 2 Phase 3
Industry – FDA Interactions
During Development
Pre-IND Meeting Safety UpdateEnd of Phase
2a Meeting Initial
IND Submissions
End of Phase 2 Meeting
BLA or NDA Application Submission
Pre-Biologic License Application (BLA) or New Drug Application (NDA) Meeting
Ongoing Submission
IND Review Phase Application Review Phase