It depends on the clinical study. An investigational new drug (IND) application is usually required when the study involves either:

(i) a new or investigational drug (i.e., not approved for marketing in the U.S.); or
(ii) an approved drug where the investigation is intended to support a change to the existing FDA approval for indication, labeling, or advertising; or
(iii) an approved drug used in a way that may increase the risks associated with the approved use of the drug product, such as a change in dosage or route of administration.

Regulations detailing the need for an IND are found at 21 CFR 312.2.

Certain studies involving a lawfully marketed (FDA-approved) drug or biological product, or a combination of approved products, may be IND exempt. This may occur when a study is not intended to support a change in marketing, labeling, or advertising for the product, and the product is not being used in a way that significantly increases the level of risk (or decreases the acceptability of risk) associated with its use. The following FDA Guidance for Industry documents discuss some scenarios when an IND is NOT needed for the study of an approved product as a treatment for cancer:

IND Exemptions for Studies of Lawfully Marketed Drug or Biological Products for the Treatment of Cancer

Investigational New Drug Applications (INDs)-Determining Whether Human Research Studies Can Be Conducted Without an IND

Whether or not an IND is required, you must comply with all regulations regarding IRB approval and subject informed consent.

You may contact Regulatory Affairs for assistance in determining whether an IND is required, or whether to contact the FDA for additional guidance.

Clinical Research Support Regulatory Affairs can assist you in requesting guidance from FDA or submitting an IND application for assessment of whether your clinical trial is IND exempt. This will require providing information to the appropriate review division, including:

• The name, brief description, and currently approved usage of the investigational product.
  
• Study information including the purpose, hypothesis, number of subjects, patient population, condition, or disease (if applicable), planned use of the product, and how this differs from the approved usage.
  
• An explanation of why you consider the product safe for administration to human subjects under the conditions of the study. 

It depends. The primary purpose of a pre-IND meeting is to review and reach agreement on the (i) design of pre-clinical studies; (ii) design of a clinical study; or (iii) chemistry, manufacturing, and controls (CMC) issues for an investigational new drug/biologic/gene therapy product, etc. These meetings are not mandatory but are often useful to obtain valuable feedback from the FDA before a formal IND is submitted.

Pre-IND meetings are usually scheduled approximately 60 days after the request is submitted to FDA, and a complete pre-IND package needs to be submitted to the FDA 30 days prior to the meeting. A pre-IND meeting request must be based on specific questions for FDA, not a request for general discussion about the proposed research.

FDA has issued a detailed draft guidance on meetings between the FDA and IND sponsors, including pre-IND meetings. Additional information Details regarding pre-IND meetings and the pre-IND package that focus on chemistry, manufacturing, and controls information for an IND submission can also be found at the FDA's website.

A more detailed description of pre-IND meeting and pre-IND package is outlined for anti-viral products, some of which are applicable for drugs and biologics. 

Regulatory Affairs can assist with preparing a pre-IND meeting submission and identifying the appropriate FDA contact information for submission.

If the study involves a drug, the IND will be reviewed by the Center for Drug Evaluation and Research (CDER). Therapeutic biological products such as antibodies are also reviewed by CDER.

If the clinical study involves a biologic (cell or gene therapy products, human tissue products, vaccines, etc.), the IND will by reviewed by the Center for Biologics Evaluation and Research (CBER).

Research INDs, such as those submitted by sponsor-investigators who are not developing a product for commercialization, do not have to adhere to the strict formatting requirements for commercial INDs that must follow the highly technical structure for electronic Common Technical Document (eCTD) submissions.

The online CDER NextGen Portal is the preferred submission method to CDER for Research INDs. Please review the CRS CDER NextGen Portal Guidelines  document for further information, and contact CRS Regulatory Affairs with additional questions.

CBER accepts Research IND submissions as PDF documents submitted via email to CBERDCC_eMailSub@fda.hhs.gov.

Both CDER and CBER will accept hard copy submissions of Research IND applications, if the preferred submission methods above are not possible. If hard copies are necessary, they must be submitted in triplicate (original plus two copies).

For drugs overseen by CDER, the application is sent to:

Food and Drug Administration
Center for Drug Evaluation and Research
Central Document Room
5901-B Ammendale Rd.
Beltsville, MD 20705-1266

For therapeutic biological products overseen by CDER, the application is sent to:

Food and Drug Administration
Center for Drug Evaluation and Research
Therapeutic Biological Products Document Room
5901-B Ammendale Rd.
Beltsville, MD 20705-1266

For biologics, the application is sent to:

Food and Drug Administration
Center for Biologics Evaluation and Research
Document Control Center
10903 New Hampshire Avenue
WO71, G112
Silver Spring, MD 20993-0002

Upon receipt of the IND by FDA, an IND number will be assigned and the application will be forwarded to the appropriate reviewing division. The reviewing division will send a letter to the Sponsor-Investigator providing notification of the IND number assigned, date of receipt of the original application, address where future submissions to the IND should be sent, and the name and telephone number of the FDA Regulatory Project Manager (RPM) to whom questions about the application should be directed.

Your IND is in effect, and you may begin your clinical trial, 30 calendar days after FDA receives your IND application unless FDA notifies you of a clinical hold. FDA may contact you within the initial 30-day review period to request additional information or changes to the proposed clinical trial. If FDA is not satisfied with the information provided, they may put the IND on clinical hold until all the issues are resolved. If a clinical hold is placed before the end of the 30-day review period, FDA must receive your complete response to the hold and issue a formal letter removing the hold in order for the IND to go into effect and the clinical trial to begin.

The FDA may issue a "Study May Proceed" letter or email as notification that the IND is in effect. FDA does not use the term “approval” when a new IND is authorized to proceed.

Yes, if the investigation is governed by FDA regulations [see 21 CFR 56.101, 56.102(c), 312.2(b)(1), 361.1, 601.2, and 812.2]. IRB review and approval is required regardless of whether the clinical investigation requires an IND. 

The FDA website includes information specifically targeted to individuals who are conducting research under investigator-sponsored INDs.

FDA also provides a series of video presentations on INDs and other topics. These sites are good resources for either an overview or more in-depth information:

Center for Drug Evaluation and Research “CDERLearn”

Office of Therapeutic Products "OTP Learn"

Training and Continuing Education

Expanded access is the use of an investigational drug outside of a clinical trial to treat a patient with a serious or immediately life-threatening disease or condition who has no comparable or satisfactory alternative treatment options. Detailed information is provided on the FDA’s website for Expanded Access.

Criteria for all expanded access uses:

1. Patient(s) must have serious or immediately life-threatening disease/condition and no comparable or satisfactory alternative therapy.

2. Potential benefit justifies potential risks, and potential risks are not unreasonable in the context of disease/condition.

3. Access will not interfere with clinical investigations to support marketing approval of the expanded access use.

Expanded access may apply to treatment of an individual patient (sometimes called "compassionate use" or a “single patient IND”) or to multiple patients. An IND for treatment of one patient is typically held by the treating physician, and may be designated as either emergency or non-emergency use. An IND for treatment of an intermediate-size group of patients may be held by an individual physician/investigator or by the company providing the investigational product. A large-scale “treatment IND” to allow widespread use of the product would be held only by a company. 

For the complete FDA regulation, please click here . A Guidance for Industry titled “Expanded Access to Investigational Drugs for Treatment Use – Qs & As” was updated by the FDA in October 2017.

We encourage you to contact Regulatory Affairs/Clinical Research Support for specific information and individualized support if you are considering submitting an Expanded Access IND. Regulatory Affairs can provide general guidance and recommendations if you are unsure how or whether to pursue an expanded access IND. When a specific patient and potential treatment have been identified, please also complete and submit the Expanded Access Individual Patient Intake Form to provide basic information.

To transfer an IND to a new sponsor, the existing sponsor submits a letter as an IND amendment to the FDA stating that IND sponsorship is transferred to the new sponsor, identifying the effective date of the transfer, and stating whether there is any outstanding business with FDA under the IND. The new sponsor submits a separate letter to the FDA under a consecutively numbered Form FDA 1571, accepting the sponsorship and its obligations, informing the FDA about the contact information of the new sponsor, indicating any planned changes under the IND in association with the new sponsorship, and confirming they have received all IND records from the previous sponsor.

A sample IND Transfer Letter and information on how to complete the Form 1571 can be obtained from the Regulatory Affairs office.

An IND sponsor can transfer responsibility for conducting any or all of the IND sponsor obligations to another party, such as a contract research organization. Any such transfer shall be described in writing and submitted to FDA under the IND. 

If not all obligations are transferred, a the description must include the specific obligations being assumed by the contract research organization or other party. If all obligations are transferred, a general statement that all obligations have been transferred is acceptable. Any obligation not covered by the written description shall be deemed not to have been transferred.

Although the IND sponsor may transfer the obligation to complete required activities to another party, the sponsor retains ultimate responsibility for ensuring that all obligations are adequately met. 

A sponsor must submit information for the IND in the following order:

1. Cover sheet (Form FDA-1571)
2. Table of Contents
3. Introductory Statement and General Investigational Plan
4. [(Reserved) — Previously, the FDA separated the Introductory Statement from the General Investigational Plan. Since they are combined currently, this section is left "blank".]
5. Investigator's Brochure (not needed for investigator-sponsored single-site studies)
6. Protocol Information
   a. Protocol document
   b. Informed consent form: not required by regulations, but routinely requested by FDA if not included in the initial submission.
   c. Form FDA 1572: Statement of Investigator
   d. Investigator's Curriculum Vitae
7. Chemistry, Manufacturing and Control Information
8. Pharmacology and Toxicology Information
9. Previous Human Experience
10. Additional Information - refers to specific categories of information when applicable, including:
    a. Potential for drug dependence or abuse
    b. Radioactive drugs
    c. Pediatric studies

In addition, the sponsor needs to submit a completed Form FDA 3674 (Certification of Compliance with Requirements of ClinicalTrials.gov Data Bank), which can be found online at the FDA forms page.

The IND application may include a limited number of selected publications that are cited in the IND and provide a significant foundation for the research to be conducted.

An IND application for use of a product that is provided by another manufacturer may be able to refer to the manufacturer’s IND for the information required by sections 7, 8, and 9 above.

Each submission relating to an IND must include a Form FDA 1571 cover sheet document with a sequentially numbered four-digit serial number. The initial IND submission is numbered as 0000; subsequent submissions are numbered as 0001, 0002, etc.

Details of an IND submission can be found in the FDA regulations at 21 CFR 312.23 and also at the FDA website. Additional information, as well as some sample and template documents, may be requested from Regulatory Affairs.

Form 1571 is an FDA form titled “Investigational New Drug Application (IND)” that accompanies the initial IND submission and each subsequent submission to the IND. 

Forms and instructions are located on the FDA Forms page.

Form 1572 is an FDA form titled “Statement of Investigator” that contains information about the investigator of the study. The clinical investigator (principal investigator) must complete Form 1572 including locations where the study will be conducted, the institutional review board (IRB) of record, and sub-investigators who will make a direct and significant contribution to the study conduct and data. Signing the Form 1572 is a formal commitment by the investigator to follow all FDA regulations associated with conducting a clinical trial. Investigators may participate in an investigation only after they provide the sponsor with a completed, signed Form 1572. 

Forms and instructions are located on the FDA Forms page. 

Form 3674 is an FDA form titled "Certification of Compliance" that confirms all applicable requirements of 42 USC § 282(j) for registration of the study on ClinicalTrials.gov are being met. This form must be submitted with an initial IND application and with any new protocol that is submitted under an existing IND.

Forms and instructions are located on the FDA Forms page.

Many trials are registered in ClinicalTrials.gov by Clinical Research Support. Additional information can be found on Clinical Trial Registries or by contacting the ClinicalTrials.gov Administrator with questions.

Form 3500A is used for MANDATORY reporting of adverse events under FDA’s MedWatch program. Mandatory reporting is required for certain types of safety information under an IND.  Note this is not the same as Form 3500, which is used for voluntary reporting of adverse events associated with approved products.

Forms and instructions are located on the FDA Forms page. 

Current good manufacturing practices (cGMP) are a set of regulations described in 21 CFR Parts 210, 211, 610. These regulations are in place to ensure that the manufacturing of a drug or biologic yields a product that is safe, effective, characterized, consistent, and pure.

FDA has compiled a number of frequently asked questions (FAQs) describing how to best comply with cGMP for drugs.

It depends. Some investigational drug/biologics used in a Phase 1 study are exempt from the cGMP requirements as specified in 21 CFR 211. These investigational agents need to follow the requirements described in the following guidance document.

The Biologics Production Facility and Cell Processing Facility, both part of the Fred Hutch/UW Cancer Consortium Therapeutic Products Program, operate in accordance with cGMP regulations and guidance to provide investigational products for use in clinical trials.

The "sponsor" is a person who holds the IND, takes responsibility for, and initiates a clinical investigation. The sponsor may be an individual, pharmaceutical company, governmental agency, academic institution, private organization, or other organization. The sponsor does not actually conduct the investigation unless the sponsor is a sponsor-investigator.

Sponsors are primarily responsible for:

1. Selecting qualified investigators and providing them with the information they need to conduct an investigation properly;
2. ensuring proper monitoring of the investigation(s), ensuring that the investigation(s) is conducted in accordance with the general investigational plan and protocols contained in the IND;
3. maintaining an effective IND with respect to the investigations; and
4. ensuring that FDA and all participating investigators are promptly informed of significant new adverse effects, risks, or other safety information with respect to the drug.

Sponsor obligations are described in the Code of Federal Regulations under 21 CFR 312.50-59, and in Section 5 of ICH GCP guidelines.

The "investigator" is an individual who actually conducts a clinical investigation (i.e., under whose immediate direction the drug is administered or dispensed to a study subject). In the event an investigation is conducted by a team of individuals, the investigator is the responsible leader of the team. "Sub-investigator" includes any other individual member of that team.

An investigator is primarily responsible for:

1. ensuring that an investigation is conducted according to the signed investigator statement, the investigational plan, and applicable regulations;
2. protecting the rights, safety, and welfare of subjects under the investigator's care;
3. maintaining control of drugs under investigation; and
4. obtaining the informed consent of each human subject to whom the drug is administered.

Investigator obligations are described in the Code of Federal Regulations under 21 CFR 312.60-69, and in Section 4 of ICH GCP guidelines. 

FDA has issued an important Guidance for Industry that further describes investigator responsibilities. 

The IND regulations require that records be retained for a period of two years following the date a marketing application is approved for the drug for the indication for which it is being investigated; or, if no application is to be filed or if the application is not approved for such indication, until two years after the investigation is discontinued and FDA is notified. The FDA expects sponsors and investigators to adhere to any local, institutional, or IRB requirements that specify a longer record retention period.

Both investigators and sponsors are required to permit FDA inspection of records and reports.

Based on FDA's findings during bioresearch monitoring (BIMO) inspections, the most common mistakes made by investigators are:

1. Failure to follow the protocol (examples: deviations, noncompliance, missed study procedures or evaluations, enrollment of ineligible subjects).
2. Incomplete or inaccurate records (examples: not retaining significant correspondence, obliterating original data when correcting source documents or CRFs, backdating signatures).
3. Inadequate drug accountability (examples: inventory discrepancies in drug accountability logs, incomplete drug diaries, temperature excursions in location where drug is stored).
4. Failure to obtain informed consent (examples: subjects not re-consented with an informed consent form that contains new risk information, inability to show that informed consent was given before a study procedure occurred on the same day).
5. Inadequate IRB communication (examples: delay in submitting revised study materials to IRB, failure to report noncompliance or unanticipated problems per IRB requirements).
6. Inadequate subject protections based on failure to report adverse events (also includes failure to record and/or assess AEs).

Issues that occur rarely but carry severe consequences include violation of human subject protections (such as not obtaining informed consent prior to participation, or preventing a subject from withdrawing), intentional falsification of data, and failure to supervise a clinical trial to the extent that subject safety or data integrity are affected.

Submission of new information to an existing IND is considered an amendment to the IND. There are three primary types of IND amendments defined by regulations: (a) protocol amendments, (b) information amendments, and (c) IND Safety Reports.

A protocol amendment is required when there is one of the following:

• New protocol
• Changes to a protocol
• New investigator

An information amendment contains essential information regarding the IND that is not within the scope of a protocol amendment, IND safety report, or annual report. Examples include:

• New toxicology, chemistry, or other technical information
• A report regarding the discontinuation of a clinical study

IND Safety Reports are required in the following situations:

• An adverse event occurs that is a serious, unexpected, suspected adverse reaction (SUSAR). Suspected adverse reaction means there is a reasonable possibility the event was caused by the use of the drug/biologic.
• There is a finding in laboratory animals or in vitro testing that suggests a significant risk to human subjects.
• Clinical, epidemiological, or pooled analysis of multiple studies suggest a significant risk to human subjects.

A serious adverse event is any adverse experience that results in:

• Death;
• A life threatening experience;
• Inpatient hospitalization or prolongation of existing hospitalization;
• A persistent or significant disability/incapacity;
• A congenital anomaly; or
• Requires intervention to prevent permanent impairment or damage.

Complete FDA regulations for IND safety reporting are at 21 CFR 312.32. A guidance document on safety reporting was also issued by FDA in December 2012. In June 2021, FDA released draft guidance with further recommendations for sponsors and sponsor-investigators to comply with the requirements of IND safety reporting. FDA also released draft guidance to help clinical investigators comply with safety reporting requirements in September 2021 and hosted a webinar on this topic shortly thereafter.  

An adverse event is reportable as an IND Safety Report only if it meets all of these criteria:

• serious (described above),
• unexpected (not described in the Investigator’s Brochure or other documented risk information such as the package insert, protocol, or informed consent form), AND
• has a reasonable possibility of being caused by the study drug/biologic (“suspected adverse reaction”) or is definitely caused by the study drug/biologic (“adverse reaction”).

IND Safety Reports must be submitted as soon as possible, but no later than 15 calendar days after the sponsor's initial receipt of the information.

In case of an unexpected fatal or life-threatening adverse event that is associated with the use of the drug/biologic, reports must be made by phone or fax as soon as possible but no later than seven calendar days after the sponsor's initial receipt of the information.

The sponsor is also required to submit follow-up information to a safety report as soon as the relevant information is available.

SAEs that do not meet criteria for IND Safety Reporting should be reported to FDA as part of the annual report to the IND.

An annual report is a summary of the progress of the clinical investigation(s) under the IND and other information obtained during the previous year's clinical and non-clinical investigations. A sponsor must submit the annual report within 60 days following the anniversary date that the IND went into effect. For example, if an initial IND submission was received by FDA on March 16, 2022, and FDA did not have any comments or questions, then the IND went into effect on April 15, 2022 (after the 30-day review period). Thus, the annual report is due on or before June 14, 2023 and by June 14 of each subsequent year.

The format and content of the annual report is described in 21 CFR 312.33.

A medical device is defined as "an instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other similar or related article, including a component part, or accessory which is:

• recognized in the official National Formulary, or the United States Pharmacopoeia, or any supplement to them,
• 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, or
• intended to affect the structure or any function of the body of man or other animals, and which does not achieve any of its 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."

This definition provides a clear distinction between a medical device and other FDA-regulated products such as drugs. If the primary intended use of the product is achieved through chemical action or by being metabolized by the body, the product is usually a drug. In vitro diagnostic assays, or IVDs, are also regulated as devices. 

The FDA regulates medical devices to assure their safety and effectiveness, and develops and carries out a national program designed to control unnecessary exposures to, and assure safe and efficacious use of, ionizing and non-ionizing radiation-emitting electronic products. The Center for Devices and Radiological Health (CDRH) is the component within the FDA that is responsible for this program. Most of FDA's medical device and radiation-emitting product regulations are in Title 21 CFR Parts 800-1050. These final regulations codified in the CFR cover various aspects of design, clinical evaluation, manufacturing, packaging, labeling and post market surveillance of medical devices. In addition, the regulations address standards and product reports that apply to radiation-emitting products.

Many clinical trials on medical devices are conducted under Investigational Device Exemptions (IDE), which are described under 21 CFR 812. A clinical trial of a device that is classified as “significant risk” requires submission of a complete IDE application to FDA. A clinical trial using a device that is deemed by the reviewing IRB not to represent “significant risk” must comply with certain IDE regulations but may not require an IDE submission to FDA (“abbreviated requirements” under 21 CFR 812.2(b)). Certain trials may be exempt from these regulations, as described under 21 CFR 812.2(c).

Determination of the regulatory pathway for a study using an investigational device relies on assessment of the device itself and the manner in which the device is used in the study. Please contact CRS Regulatory Affairs if you would like assistance in assessing how IDE regulations may impact your study.

The IDE application is somewhat similar to the IND application (for drugs and biologics) and it is submitted to the Center for Devices and Radiological Health (CDRH).

Detailed information on the contents of an IDE application is provided on the FDA website.

IDE submissions must be provided on electronic media and formatted as required by the CDRH eCopy program. FDA has issued a Guidance for Industry and FDA Staff on the eCopy Program for Medical Device Submissions.

FDA will notify the sponsor in writing of the date the application is received and will issue approval or disapproval of the IDE application within 30 days following their receipt of the IDE application. FDA may also request additional information during this time. Unlike an IND, you may not begin conducting a clinical trial under an IDE until you have been notified of FDA approval of the IDE.

A pre-IDE meeting is not required. However, if a sponsor has specific questions for FDA before submitting their IDE, a Pre-Submission request may be submitted. FDA describes how to obtain feedback on different device-related issues in the guidance Requests for Feedback and Meetings for Medical Device Submissions: The Q-Submission Program. 

Not exactly. Many of the sponsor responsibilities are roughly equivalent, such as monitoring the conduct of clinical trials conducted under the IDE and submitting required reports to FDA. However, there are some notable differences including the specific reporting obligations to FDA.

Before deciding to submit an IDE application for a clinical trial using a significant risk medical device, a potential sponsor should review the relevant regulatory obligations under 21 CFR 812 including Subpart C: Responsibilities of Sponsors, Subpart E: Responsibilities of Investigators, and Subpart G: Records and Reports.

A very useful website for medical devices is FDA’s "Device Advice".

Guidance documents are published by the FDA to provide interpretation of regulations. These documents do not establish any legally enforceable responsibilities. They describe FDA's current thinking on a topic and should be viewed as recommendations, unless specific regulatory or statutory requirements are cited. On a practical note, it is a good idea to follow the recommendations made in the guidance documents.  See our “Helpful Links” section for frequently used guidance documents related to conducting clinical trials.

Each guidance document includes the following "disclaimer" by FDA:

"This guidance represents the Food and Drug Administration's (FDA's) current thinking on this topic. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. You can use an alternative approach if the approach satisfies the requirements of the applicable statutes and regulations. If you want to discuss an alternative approach, contact the appropriate FDA staff. If you cannot identify the appropriate FDA staff, call the appropriate number listed on the title page of this guidance."

A Drug Master File (DMF) is a submission to the FDA that may be used to provide confidential detailed information about facilities, processes, or articles used in the manufacturing, processing, packaging, and storing of one or more human drugs.

DMFs are generally created to allow a party other than the holder of the DMF to reference material without disclosing to that party the contents of the file, such as a contract manufacturer. There are several categories of DMF depending on the nature of the information it contains.

Reference