IND and IDE Submissions
Investigator Responsibilities under IND and IDE
As a consequence of increased volume of investigator-initiated clinical research involving drugs and/or devices, there are numerous institutional considerations to ensure that investigators and their research staffs are appropriately equipped to manage all aspects of the regulatory responsibilities and obligations associated with initiating and conducting such research.
1. Sponsor and Investigator Responsibility checklist with supporting documents (Partners Human Research Quality Improvement (QI) Program)
2. Understanding FDA Regulatory Requirements for Investigational New Drug Applications for Sponsor-Investigators (M. E. Blair Holbein, PhD, J Inv Medicine (2009), v. 57, n. 6, p. 689-695).
FDA receives frequent inquiries from the academic community about whether an IND should be submitted for various types of clinical research. Examples of such inquiries include:
- Clinical investigations using marketed drugs
- Bioequivalence/bioavailability studies
- Studies using radiolabeled or cold isotopes
- Studies using dietary supplements or foods
- Studies using endogenous compounds
- Pathogenesis studies using modified organisms
- Studies using wild-type organisms in challenge models
It is important to note that the drug definition is not limited to compounds intended for a therapeutic purpose. The definition also includes compounds intended to affect the structure or function of the body, without regard to whether the compound is intended to influence a disease process.
The definition also includes compounds used for research purposes in healthy subjects to blunt or provoke a physiologic response or study the mechanism of action or metabolism of a drug.
A dietary supplement intended only to affect the structure or function of the body and not intended for a therapeutic purpose is not a drug.
A clinical investigation of a marketed drug is exempt from the IND requirements if all of the criteria for an exemption in § 312.2(b) are met:
- The drug product is lawfully marketed in the United States.
- The investigation is not intended to be reported to FDA as a well-controlled study in support of a new indication and there is no intent to use it to support any other significant change in the labeling of the drug.
- In the case of a prescription drug, the investigation is not intended to support a significant change in the advertising for the drug.
- The investigation does not involve a route of administration, dose, patient population, or other factor that significantly increases the risk (or decreases the acceptability of the risk) associated with the use of the drug product (21 CFR 312.2(b)(1)(iii)).
- The investigation is conducted in compliance with the requirements for review by an IRB (21 CFR part 56) and with the requirements for informed consent (21 CFR part 50).
- The investigation is conducted in compliance with the requirements of § 312.7 (i.e., the investigation is not intended to promote or commercialize the drug product).
The potential academic sponsor-investigator is responsible for determining whether the investigation meets the criteria for an exemption. If there is uncertainty about whether the exemption criteria are met, the sponsor-investigator can seek advice from FDA for determination (§ 312.2(e)).
For more information read a very helpful FDA Guidance "Investigational New Drug Applications (INDs)- Determining Whether Human Research Studies Can Be Conducted Without an IND."
For further assistance with IND determinations and FDA communications, contact Clinical Trials Resource Group.
1. Contact CTSC for assistance with IND applications, if needed
2. Create the study protocol using one of the accepted industry templates. Language and format used for grants is not acceptable
3. Prepare IND package using templates and examples below. Allow at least 4-6 weeks for IND preparation, collation, pagination, copying etc.
- Cover Letter (Example)
- IND (Template, Example). Sometimes the manufacturing information (CMC Section) can be abbreviated if: a) a letter of authorization to cross-reference the original IND is available, or b) if the drug is approved and product insert is available
- Protocol and Investigator Brochure templates can be found on the "Helpful Templates" page
- Fill out Form 1571, Investigational New Drug Application (Example). When downloading this form from the FDA website, note the OMB expiration date in the upper right corner. You form will not be accepted if it is past the expiration date. Instructions for filling out the Form1571 can be found here
- Fill out Form 1572, Statement of the Investigator (Example). Please read Frequently Asked Questions about Form 1572.
- Fill out Certification Form 3674 (Clinicaltrials.gov attestation). Typically, you must submit the form 3674 with a new IND. Protocol amendments will require resubmission of this form (Example). If you plan to upload your trial to Clinicaltrials.gov, but have not done it yet, mark box b. For instructions on how to fill out, click here.
- Assemble and bind volumes into plastic binders. Each binder must be labeled using the FDA format (Template)
4. Each Submission should contain: a signed cover letter, and the fully assembled IND document with Tabs. Submit one original with wet signatures and 2 paper copies of the entire submission. Include 3 eCopies with the submission (on CDs, DVDs, or flash drives). Each eCopy will have two files: "001_CoverLetter" and "002_Investigational Drug Application". Contact Clinical Trials Office for assistance with eCopy.
5. Send to:
Food and Drug Administration
Center for Drug Evaluation and Research
Central Document Room
5901-B Ammendale Rd. Beltville, MD 20705-1266
Start with the FDA Website "Device Advice: Investigational Device Exemptions"
Download the comprehensive summary of device classification, regulations, IDE submissions, Humanitarian use designation etc.
A medical device is:
"an instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other similar or related article, including a component part, or accessory which is:
intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment, or prevention of disease, in man or other animals,
intended to affect the structure or any function of the body of man or other animals, and which does not achieve any of it's primary intended purposes through chemical action within or on the body of man or other animals and which is not dependent upon being metabolized for the achievement of any of its primary intended purposes."
IMPORTANT: the clinical study of a new indication for an already marketed device falls under the IDE regulation.
Some studies may be exempt from the IDE regulations (21 CFR 812.2(c)), if:
1. a legally marketed device when used in accordance with its labeling,
2. a diagnostic device if it is:
• does not require an invasive sampling procedure that presents significant risk;
• does not by design or intention introduce energy into a subject;
• and is not used as a diagnostic procedure without confirmation by another medically established diagnostic product or procedure;
3. consumer preference testing…of legally marketed device(s)
4. a device intended solely for veterinary use;
5. a device shipped solely for research with laboratory animals
• Study approved by an institutional review board (IRB). If the study involves a significant risk device, the IDE must also be approved by FDA;
• Informed consent from all patients obtained and documented;
• The device is labeled “CAUTION- Investigational Device. Limited to investigational use only”
• Sponsor-investigator complies with monitoring requirements
• Records and reports are maintained
How to file an IDE with the FDA
The IDE submission includes:
• Cover Letter
Content of the Cover Letter:
1. A statement that this is an original IDE application
2. Device information: a brief overview of the device
3. Sponsor-investigator contact information;
4. Device manufacturer information;
5. Applicant information (who submits this application);
6. Other relevant information (e.g. prior discussions with the FDA)
Content of an IDE Application:
1. Table of Contents
2. Report of prior investigations (including animal work)
3. Investigational plan
4. Risk analysis (in a table format)
5. Description of the device
6. Monitoring procedures
7. Manufacturing information
8. Sponsor-investigator information, including CV
9. IRB information
10. Sales information
11. Environmental impact statement
13. Informed Consent materials
14. Other information as pertinent
Use this IDE Template to generate IDE Application. The template expands each section in greater details.
Template for Investigator Agreement and Financial Disclosure
Template for Investigator Certification
Clearly and prominently identify submission as original IDE application or, for additional submissions to an IDE application, clearly identify the FDA assigned document number (e.g., G960000) and the reason for the submission (e.g., amendment or supplement) and the type of submission (e.g., Response to FDA letter; Addition of New Institution, etc.).
Use FDA Guidnace for PDF Specifications to create your PDF file
Make 3 identical copies of each submission
In addition, the sponsors must provide an eCopy per Guidance "eCopy Program for Medical Device Submissions."
Ready to submit? Use a helpful checklist for IDE Application
UCSF’s Clinical and Translational Science Institute has assessed and pre-selected a number of Contract Research Organizations (CROs) that offer a broad range of key research services. The CROs have been chosen on the basis of their proven technical expertise, flexibility, past experience in working with academic investigators, and price. UCSF offers a referral service to UC Davis investigators.
Currently pre-selected CROs offer a broad spectrum of expertise and services, including (but not limited to):
- High-throughput screening
- ADME (in vitro and in vivo)
- Pharmacokinetics and pharmacodynamics
- Toxicology (including GLP tox)
- Bio/analytical services
- Medicinal Chemistry and custom synthesis
- GMP manufacturing
- Preclinical disease models
- Biocompatibility (for device development)
Additional CROs with device development expertise are currently being identified.
To get connected to a CRO, see UCSF website or contact Irina Gitlin (email@example.com or 415-514-8510).
Expanded Access or compassionate use is the use of investigational drug outside of a clinical trial for the sole purpose of treating a patient or patients with serious or life-threatening disease who have no acceptable medical option. Serious diseases or conditions are those associated with morbidity that has a substantial impact on day-to-day functioning. Whether a disease is serious is a matter of clinical judgment. Examples cited by FDA include epilepsy and in situ breast cancer.
Expanded Access includes three options:
• Treatment IND
• Group C treatment IND
• Emergency Use IND
In June 2016, the FDA came out with the final Guidance document "Individual Patient Expanded Access Applications: Form FDA 3926" for the expanded access for the compassionate use of investigational drugs. The FDA also release the new Form 3926 that physicians fill out to apply for expanded access
The more general Q&A on expanded access also gives a detailed breakdown on the basics of expanded access, or what was previously known as compassionate use, the forms used, who can make a submission (sponsor of an IND or a licensed physician), why expanded access might be denied and other situations, including emergencies can be found in the Guidance Expanded Access to Investigational Drugs for Treatment Use – Questions and Answers:
- Who can make a submission?
- What are the roles of the patient’s physician and FDA ?
- When should individual patient access be requested?
- When can emergency use access begin?
- And more....