Investigational Drug Protocols

What information does the IRB need to know before approving your drug study?

  • Does the study involve the use of a drug in one or more persons?
  • Does the protocol involve the use of an approved drug or a drug used in the course of medical practice?
  • Is the drug being used for investigational purposes or off-label?
  • Does the investigator have intentions to market the drug or change its current label
    • *See definitions section for italicized terms

ESTR SmartForm Sub-Section: Drugs

Identify all drugs, biologics, foods and dietary supplements (approved and unapproved) being used in the Human Research. For each, indicate whether it has an IND number and for those that do, ensure that the application includes one of the following: (a) sponsor protocol with the IND number; (b) communication from the sponsor with the IND number; or (c) communication from the FDA with the IND number. Additionally attach the following items:

  • Investigator Brochure for each investigational drug involved in the Human Research
  • Current Package Insert (Submit for each marketed drug involved in the Human Research)
  • Validation of IND#  (e.g. FDA Approval letter or Sponsor Protocol)

Definitions

Drug – Product intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease – meets the definition of a drug per the FD&C Act (201(g)(1) – substance (other than food) intended to affect the structure or any function of the body.

Investigational Drug  – 1) A product that is not approved (for marketing) in the US as a drug.  2) Approved drug that is not used according to the approved label or used in a new combination of approved drugs.

Note: Practice of medicine allows a physician to use any approved drug for treatment purposes without prior regulatory approval (e.g. – FDA Submission).

Investigational New Drug (IND) application: a request to the FDA for authorization to administer an investigational drug (or biologic) to humans or a marketed drug in a new indication and/or patient population.

Commercial Drugs – Products that are approved for marketing in the US as drugs; used according to the drug labeling. IND requirements depend on whether product is/is not used according to label (printed material that accompanies a drug) and/or there is increase risk associated with change to label.

On-label Use: Drug label refers to the printed material that accompanies a drug (including package insert). When a drug is used ” On-label” the same indication, dose, route of administration, patient population, and/or drug formulation is used in the research study that is listed on the package insert.

Note: Studies involving the on-label use of a drug do not require an IND but still need to go through the IRB review process.

Sponsor is an individual, company, academic institution, or other organization that takes responsibility for and initiates a clinical investigation

Investigator is an individual who conducts a clinical trial under whose immediate direction a drug is administered or dispensed

Sponsor-Investigator is an individual who both initiates and conducts an investigation, and under whose immediate direction a drug is administered or dispensed.

IND Exemptions

The following 5 criteria must be met for IND exemptions:

  1. The study is not designed to support approval of a new indication or a change in label.
  2. The study is not intended to support a significant change in the advertising for the product.
  3. 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 for investigational drugs.

Note: Investigators can make IND exemption determinations but he/she should submit a rational to the IRB for approval of the exemption.  If the IRB does not agree, the investigator can contact the FDA for additional guidance and supporting documentation to provide to the IRB.

IND Preparation and Maintenance (For Sponsor-Investigators)

Note: If the IRB determines an IND submission to the FDA is required for the submitted IRB protocol, then the investigator becomes the Sponsor-Investigator and is responsible for submitting and maintaining the IND.

IND Format and Content (Submit original application containing the sections below to the FDA with 2 photocopies)

  • Form 1571 (cover sheet)
  • Form 3674 (ClinTrials.gov registration)
  • Table of Contents
  • Introductory Statement
  • General Investigation Plan
  • Investigator’s Brochure
  • Protocols (Includes Informed Consent & PI’s CVs)
  • Chemistry, Manufacturing and Control Data (CMC)
  • Pharmacology and Toxicology Data
  • Previous Human Experience
  • Additional Information

Note: Bolded sections can be referenced to drug labeling or to letters of authorization (cross reference letter from a sponsor/company to their IND or Drug Master File) stating that confidential information from their submission can be used in support of the submission; This allows FDA to reference these sections for the application.

Where to submit initial IND submission (for Sponsor-Investigators)

For a Drug (CDER):
U.S. Food and Drug Administration, Center for Drug Evaluation and Research, Central Document Room, 5901 Ammendale Road, Beltsville, MD 20705-1266

For a Biologic (CBER):
U.S. Food and Drug Administration, Center for Biologic Evaluation and Research,  Document Control Room, 10903 New Hampshire Avenue, Building 71, Room G112, Silver Spring, MD 20993-0002

Note: FDA will respond within 30 days via an ‘Acknowledgement letter‘ with the IND Number. The name of your FDA Project Manager will also be on the letter. FDA doesn’t always send a response.  If no issues are identified by day 30, the IND is considered to be in effect (i.e. approved). If issues cannot be resolved within the 30 day period the IND is considered to be on clinical hold.

IND Maintenance for Sponsor-Investigators
Sponsor-Investigators are required to submit amendments/changes (Protocol, Informational, Safety) for new information pertaining to their IND to the FDA. They are also required to provide an annual report to their IND application.  Examples of required submissions to the FDA are listed below:

Protocol – New protocol, changes in protocol that significantly affect safety, quality, and scope of the investigation. For multi-site studies obtain IRB approval letters for each site.

New Investigators – Sponsor-Investigators must collect and submit 1572 and CVs of the Principal Investigators from each site to FDA. Must be submitted within 30 days of investigator coming onboard.

Informational Amendment – Includes new technical information or discontinuation of study. Informational amendments can be lumped together. Submit in 30 day intervals.

Safety Reports – Serious (e.g. – death, life-threatening, hospitalization, significant disability or congenital anomaly) and Unexpected (not specified in Investigator’s Brochure or informed consent forms) adverse events should be reported as soon as PI is aware and has supporting documentation regarding the event (but no later than 7 days of becoming aware).

Sponsor-Investigators can report safety information via the FDA Form 3500A (MedWatch Mandatory Reporting form) or CIOMS form for international events. Note: In addition to the FDA, notify the IRB via a Report of New Information (RNI) within 5 days of becoming aware of any unanticipated events possibly related to the investigational protocol. 

Annual Reports – Due within 60 days of IND Effective Date. IND Holders are required to submit on an annual basis a summary of study safety concerns within past year, general investigational plan, outline of any protocol modifications within past year, copy of the Investigator Brochure, information regarding any foreign marketing developments, and any significant outstanding business the FDA should know about.

Ending an IND 
A Sponsor-Investigator may withdraw an IND for any reason.  Both the FDA and IRB should be notified if this becomes the case. In addition, the FDA may deactivate an IND if there is no communication (annual report updates/amendments) for 2 years.  If no IND correspondence is submitted for greater than 5 years, the FDA can terminate the IND.

Note: The FDA can also terminate an IND if there are any safety concerns with the drug.  The Sponsor-Investigator will have an opportunity to respond to this termination notification.

Requirements for New IND Holders

Following IRB approval, Sponsor-Investigators are required to contact the Quality Improvement Program to discuss their research protocol and ensure they are meeting their FDA Sponsor-Investigator Responsibilities.  Prior to the first continuing review and every 2 years following, until the protocol closes, Sponsor-Investigators are encouraged to contact QIP to conduct an onsite review of their protocol.

Tools/Checklist: