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IND & IDE Submissions

A clinical trial is most often used in conjunction with obtaining new drug (IND) or device (IDE) approval from the U.S. Food and Drug Administration, although they can be designed with the sole purpose of collecting and analyzing data about an approved drug or device in order to contribute to medical knowledge about the treatment of a disease or medical conditions.

Regulatory Requirements

Clinical studies involving a drug, biologic or dietary supplement

FDA’s Center for Drug Evaluation and Research (CDER) is responsible for regulating manufacturing, testing and importation of pharmaceutical drugs in the US. This includes new drug approvals, abbreviated new drug approvals (generics), over-the-counter drugs, animal drugs and biologics.

A drug is defined as:

  1. article intended for use in diagnosis, cure, mitigation, treatment, or prevention of the disease;
  2. articles (other than food) intended to affect the structure or any function of the body;
  3. articles intended to be used as components of any of the above.

 

Preclinical Regulatory Requirements

Preclinical testing begins after a potential drug has been identified in the lab. Preclinical testing involves lab and animal studies that evaluate the drug’s toxic and pharmacologic effects. Preclinical studies are also subject to the FDA regulations known as Good Laboratory Practices (GLP), 21 CFR 58. The GLP regulations specify minimum standards in such areas as personnel, facilities, equipment and operations.

Preclinical testing includes pharmacokinetics, the study of how the drug moves through living organisms. Researchers examine absorption, distribution, metabolism and excretion (also abbreviated as ADME) to ensure that the drug reaches its intended target and passes through the body properly. In addition to the biological tests, researchers conduct chemistry tests to establish the drug’s purity, stability and shelf life. Manufacturing tests are conducted to determine the feasibility of producing the drug on a large scale and to explore dosing, packaging and formulation (e.g., pill, inhaler, injection).

At the preclinical stage, the FDA will generally ask, at a minimum, that sponsors: (1) develop a pharmacological profile of the drug; (2) determine the acute toxicity of the drug in at least two species of animals, and (3) conduct short-term toxicity studies ranging from two weeks to three months, depending on the proposed duration of use of the substance in the proposed clinical studies.

IND Development Process

Overview

An academic researcher may be required to submit an IND application to the FDA in order to study a marketed medical product in a new (i.e. unapproved) clinical indication.  An investigator is always required to hold an IND to study an unmarketed (i.e. unapproved) medical product.  In both cases, the products are considered "investigational" by FDA.  The vast majority of INDs on file with the FDA are for noncommercial research.

 

The Pre-IND Process

Review the five requirements below to determine if your study qualifies for exemption from an IND (21 CFR 312.2).

Still not sure? Start with the IND Decision Tool. 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 you think a pre-IND meeting is warranted please contact the UCSD Office of IRB Administration for assistance.  Templates for a IND Exemption letter and pre-IND Contact list are provided below.  In addition, please consult with the IRB to determine whether a formal letter from FDA is required to document the waiver.

 

IND 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:

  • 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.
  • The investigation is not intended to support a significant change in the advertising for a prescription drug product.
  • 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.
  • The investigation is conducted in compliance with the requirements for IRB review and informed consent (IRB Handbook search "IND Exemptions")
  • 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.

For additional information about whether or not an IND is required for a cancer therapy drug you must contact the NCI Regulatory Affairs Branch.

 

The IND Study Protocol

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

Review the IND Factsheet for required content.  A completed protocol must be included in the IND application.

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. Compile a reference list - include all published articles and unpublished reports or manuscripts cited.

Collect a copy of each article or report listed. 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.

 

Prepare the Initial IND Submission

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.
    • For marketed drugs, the FDA already has this information on file in the manufacturer’s Drug Master File (DMF). For unmarketed drugs, the Investigator-Sponsor can request a Letter of Authorization (LOA) from the manufacturer to cross-reference the Drug Master File or existing IND if there is one. Although it is not required, the LOA is recommended.
    • For legally marketed drugs, the information in the product label or package insert 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.

The IND Sponsor-Investigator writes the IND in the format of IND Application Template. The initial IND submission should be accompanied by a cover letter, an IND Application Form - FDA 1571 and a ClinicalTrials.Gov Certification of Compliance - FDA 3674. (All forms optimized for Safari)

The IND Sponsor-Investigator must also submit a Statement of Investigator - FDA Form FDA 1572. This form is a formal contract with FDA to adhere to Informed Consent, IRB review, and general IND regulations.

 

File the Initial IND and Receive an IND Number

  1. The initial IND submission should be accompanied by a cover letter, a Form FDA 1571  and a ClinicalTrials.Gov Certification of Compliance - FDA 3674.
  2. All must be submitted in triplicate (an original and two photocopies):
  3. The IND Sponsor-Investigator completes, signs, and dates the Form FDA 1571
  4. The IND Sponsor-Investigator assembles the signed submission and makes three photocopies and one PDF of the original documents.

*Please Note:  Academic Institutions are not required to submit electronically. However, if you would like to submit electronically, please see the following contacts and guidance.

For an initial submission, the IND Sponsor-Investigator sends the original and two photocopies to the appropriate address via overnight courier.  Keep one copy of the submission packet as well as a photocopy of the courier airbill.

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 Rd.
Beltsville, MD. 20705-1266

On the delivery date, track the shipment on the courier website for confirmation of delivery.  Print the delivery confirmation and file it with the copy of the submission packet, which 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. The sponsor must wait 30 calendar days before initiating any clinical trials.  During this time, FDA has an opportunity to review the IND for safety to assure that research subjects will not be subjected to unreasonable risk. If there are no issues, the IND generally goes into effect 30 days after the Date of Receipt shown in this letter. It is advised that you obtain written confirmation (email or fax) that the FDA review has been completed and that the study May Proceed.

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

 

Maintain the IND

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 should have a cover letter and is a submission to an existing IND notifying the FDA of one or more of the following:

 

IND Annual Reports

An IND Annual Report requires a cover letter and 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.

 

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.

IDE Development Process

Maintain the IDE

Amendments, Safety Reports & Annual Reports (FDA Guidance)

IDE sponsor-investigators are required under 21 CFR 812.150 to submit the following reports:

Unanticipated adverse device effects (UADE)

A UADE is any serious adverse effect on health or safety, any life-threatening problem or death caused by, or associated with a device, if that effect, problem, or death was not previously identified in nature, severity, or degree of incidence in the application; or any other unanticipated serious problem associated with a device that relates to the rights, safety, or welfare of subjects.

A UADE Report consists of a completed Form FDA 3500A and an analysis of the event in a cover letter, submitted to FDA and all reviewing IRBs and investigators within 10 working days after the sponsor first receives notice of the adverse effect.  

 

Withdrawal of IRB approval

Submitted to FDA and all reviewing IRBs and participating investigators within 5 working days after receipt of notice of the withdrawal of IRB approval of an investigation (or any part of an investigation).

 

Withdrawal of FDA approval

Submitted to all reviewing IRBs and participating investigators within 5 working days after receipt of notice of any withdrawal of FDA approval.

 

Current list of investigators with addresses

Submitted to FDA every six months.

 

Progress reports

Submitted to FDA and all reviewing IRBs at regular intervals and at least yearly.  A suggested format for the Progress Report can be found on the CDRH website.

 

Recalls and device disposition

Submitted to FDA and all reviewing IRBs within 30 working days after receipt of a request to return, repair, or dispose of any unit of an investigational device. The report must state why the request was made.

 

A final report

For a significant risk device, the sponsor must submit a final report notifying FDA and all reviewing IRBs within 30 working days of the completion or termination of the investigation. The sponsor must also submit a final report to FDA and all reviewing IRBs and participating investigators within 6 months after the completion or termination of the investigation.  

 

Use of a device without informed consent

Submitted to FDA within 5 working days after receipt of notice of such use.

 

SR device determination

Submitted to FDA within 5 working days after determination by an IRB that the device is a SR device and not an NSR device as the sponsor had proposed.

Other reports

Accurate, complete, and current information about any aspect of the investigation upon request from FDA or the reviewing IRB.

 

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Regulatory Support

Regulatory Support

The ACTRI Center for Clinical Research provides assistance to investigators before protocols are submitted to regulatory agencies.  Our goal is to interact closely with investigators to help them meet regulatory requirements. Several faculty members in the Center for Clinical Research are members of Institutional Review Board (IRB) review committees and have extensive knowledge of requirements regarding human subjects. [Learn more]

 

Request Services

IRB Guidance

Experienced staff in the UCSD Office of IRB Administration can provide guidance with FDA applications. The ACTRI has staff with regulatory experience who can prepare and submit documents to the IRB, including proposals, consent forms, adverse event reports, annual and final reports, and 4-year renewals. For help with IRB submissions, please submit a ACTRI Services Request using the button above.