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