Investigational New Drug Application (IND)

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.

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

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

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

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)

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 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

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

FDA Review FDA Review Process Includes: Safety Medical/clinical Chemistry Pharmacology/ Toxicology Statistical

IND Categories Commercial Research (non-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

Other Types of INDs Emergency Use Exploratory IND Treatment IND 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.

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) (5) it is conducted in compliance with the requirements concerning the promotion and sale of drugs [21 CFR 312.7]; and (6) it does not intend to invoke 21 CFR 50.24.

IND Holder Responsibilities If an investigator submits an IND, they are responsible for following the regulations for both a Sponsor and an Investigator (Sponsor- Investigator) 21 CFR 312.3(b)

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

Investigator Responsibilities (21 CFR 312.60-68) 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 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

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

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

Information Amendments Clinical data (not protocol related) Pharmacology or toxicology data Chemistry Manufacturing and Control (CMC) information Notice of discontinuance of a clinical study

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

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

Summary of the IND Process and Interaction with FDA Basic Research Prototype Design or Discovery Preclinical Development Clinical Development FDA Filing/ Approval & Launch Preparation Phase 1 Phase 2 Phase 3 Pre-IND Meeting End of Phase 2a Meeting Safety Update Industry – FDA Interactions During Development Initial IND Submissions BLA or NDA Application Submission End of Phase 2 Meeting Ongoing Submission Pre-Biologic License Application (BLA) or New Drug Application (NDA) Meeting IND Review Phase Application Review Phase