IND Development Toolkit

1. Determine Whether You Need an IND: the Pre-IND Process

Review the five requirements below to determine if your study qualifies for exemption from an IND (21 CFR 312.2). Pay particular attention to requirement #3. The FDA Draft Guidance Investigational New Drug Applications (INDs) – Determining Whether Human Research Studies Can Be Conducted without an IND provides more detail on a range of issues, including the process for consulting with FDA if unsure.

If you think a pre-IND meeting is warranted please contact ITHS for assistance. Templates for a meeting request letter and pre-IND briefing packet are provided below. In addition, please consult with your institutional IRB to determine whether a formal letter from FDA is required to document the waiver.

22 kBRequest for IND Waiver 321 kBPre-IND Consultation Contact List26 kBRequest for Pre-IND Meeting17 kBPre-IND Briefing Packet

Exemptions

A drug that is lawfully marketed in the United States is exempt from the requirements for an IND if all of the following apply:

1. The investigation is not intended to be reported to the FDA in support of a new indication for use or any other significant change in the labeling for the drug.
2. The investigation is not intended to support a significant change in the advertising for a prescription drug product.
3. The investigation does not involve a change in route of administration, dosage level, or patient population, or other factor that significantly increases the risks (or decreases the acceptability of the risks) associated with use of the drug product.
4. The investigation is conducted in compliance with the requirements for IRB review (21 CFR 56) and informed consent (21 CFR 50).
5. The drug may not be represented as safe or effective for the purposes for which it is under investigation, nor may it be commercially distributed or sold.

2. Complete the study protocol

An IND requires a fully developed protocol.

A fully developed clinical protocol is the basis for both the IRB Application and the initial IND submission:

1. Review the protocol template for required content.  A completed protocol must be included in the IND application.
   82 kBStudy Protocol for a drug study
2. Start with a protocol synopsis (page 7 and 8 of the protocol template).  The protocol synopsis will be valuable if you are planning a pre-IND meeting.
3. Compile a reference list – include all published articles and unpublished reports or manuscripts cited.  Collect a copy of each article or report listed.
4. For approved medications, print and read the Prescribing Information.  Product information should be integrated into the protocol.  In addition, your safety plan should acknowledge known safety risks from the prescribing information and incorporate relevant safety monitoring into the protocol – or show why it is not relevant to the disease under study.

3. Prepare the Initial IND Submission

1. The IND Sponsor-Investigator compiles information in three broad areas:
   • Animal Pharmacology and Toxicology Studies:  Preclinical data used to assess whether the product is reasonably safe for studies in humans. For studies of marketed drugs in new indications, this section might contain data from animal models supporting the utility of the drug in the new indication.
   • Manufacturing Information:  The composition, stability, and controls used for manufacturing the drug substance and the drug product.
     1. For marketed drugs, the FDA already has this information on file in the manufacturer’s Drug Master File (DMF).  An Investigator-Sponsor can request a Letter of Authorization (LOA) from the manufacturer to refer to the information, although it is not required.  Consult ITHS for more information if necessary.
     2. For legally marketed drugs, the information in the product label might suffice for the manufacturing information.
   • Clinical Protocols and Investigator Brochures:  A detailed clinical study protocol, and Investigator Brochure are required sections of an IND application.  The Investigator Brochure is primarily needed for multi-center studies and is a summary of information needed by participating investigators to assess the safety of the investigational product.  For approved medications, a copy of the Prescribing Information may be used in place of an Investigator Brochure.
   • Signed Form FDA 1571.  This form is a formal contract with FDA to adhere to Informed Consent, IRB review, and general IND regulations (Form FDA 1572).
2. The IND Sponsor-Investigator writes the IND in the format of the following template.
   42 kBIND Submission

4. File the Initial IND & Receive an IND Number

1. The initial IND submission should be accompanied by a cover letter (see below), a Form FDA 1571 (see instructions) and a Certification Form 3674.
   22 kBIND Cover Letter
   All must be submitted in triplicate (an original and two photocopies):

1. The IND Sponsor-Investigator completes, signs, and dates the Form FDA 1571.
2. The IND Sponsor-Investigator assembles the signed submission and makes three photocopies and one PDF of the original documents.
3. For an initial submission, the IND Sponsor-Investigator sends the original and two photocopies to the following address via overnight courier.
   
   For a Drug
   Food and Drug Administration
   Center for Drug Evaluation and Research
   Central Document Room
   5901-B Ammendale Rd.
   Beltsville, Md. 20705-1266
   For a Therapeutic Biological Product
   Food and Drug Administration
   Center for Drug Evaluation and Research
   Therapeutic Biological Products Document Room
   5901-B Ammendale Road
   Beltsville, MD 20705-1266

• Keep a photocopy of the courier Airbill.  On the delivery date, track the shipment on the courier website for confirmation of delivery.  Print and file a copy of the delivery confirmation (select Adobe from the print menu).
• The IND Sponsor-Investigator files the .PDF and the third photocopy of the signed submission.  The IND Sponsor-Investigator’s photocopy is kept in an IND Binder.

The FDA responds to the initial submission of a new IND with a letter, acknowledging receipt of the submission and assigning the IND number.  An IND generally goes into effect 30 days after the Date of Receipt shown in this letter.

The IND Acknowledgement letter also provides the mailing address for all subsequent submissions to the IND.

5. Maintain the IND: Amendments, Safety Reports, and Annual Reports

To maintain an IND, the Sponsor-Investigator has three reporting responsibilities.  Each type of report is time-sensitive and has a specific structure.  The first two, Protocol Amendments and Safety Reports, are submitted when needed to report updated or unforeseen circumstances. The third type, the Annual Report, is submitted every year, even when no studies are in progress under the IND.  Send all submissions to the address provided in the IND Acknowledgement letter received in response to the initial submission.

IND Protocol Amendments

Once an IND is in effect, the IND Sponsor-Investigator is responsible to amend it as needed to ensure that the clinical investigations are conducted according to protocols included in the application.  An IND Protocol Amendment is a submission to an existing IND notifying the FDA of one or more of the following:

• A new study protocol
• A change in an existing study protocol
• A new investigator

Cover letters and guidance for submitting IND protocol amendments

IND Safety Reports

An IND Safety Report is expedited, written notification to the FDA of an adverse experience associated with the use of a study drug that is both serious and unexpected. “Associated with the use of the drug” is a Code of Federal Regulations term meaning, “There is a reasonable possibility that the experience may have been caused by the drug.”  An IND Safety Report consists of a MedWatch Form and a cover letter.  It is due to the FDA within 15 calendar days of initial receipt of the SAE Report.
Templates and guidance for submitting IND Safety Reports

IND Annual Reports

An IND Annual Report is a brief report of the progress of studies conducted under an IND, due annually to the FDA within 60 days of the anniversary of the date that the IND went into effect.
Template and cover letter for submitting IND annual reports