Starting and managing a study conducted under an IND or IDE involves greater risk, complication, and attention from the study team. Clinical Research Support's Regulatory Affairs group is ready to help all Consortium study teams navigate the regulations and processes laid out by the FDA.
In the information below, you'll find answers to some of the most frequently asked questions. Because of the complexity of these studies we encourage you to contact Clinical Research Support for information specific to your study.
Investigational New Drug Application (IND)
Do I need an IND?
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 (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 Guidances for Industry discuss some scenarios when an IND is NOT needed for the study of an approved product as a treatment for cancer:
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.
Do I need a pre-IND meeting?
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 in case of 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 requested 60 days in advance, and a pre-IND package needs to be submitted to the FDA 30 days prior to the meeting.
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.
Pre-IND consultation contact information can be found online.
Who do I submit my IND to?
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).
For biologics, the application is sent to:
Food and Drug Administration
Center for Biologics Evaluation and Research
Document Control Center
10903 New Hampshire Avenue
Silver Spring, MD 20993-0002
If the study involves a drug, the IND will be reviewed by the Center for Drug Evaluation and Research (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 (antibodies, cytokines, peptides etc.) transferred to 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, MF 20705-1266
What will happen after FDA receives the IND?
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 person to whom questions about the application should be directed.
After I submit an IND, when can I start the clinical trial?
You may begin your clinical trial thirty (30) days after FDA receives your IND application, unless FDA contacts you. If FDA is not satisfied with the information provided in the IND application, they may put the IND on clinical hold until all the issues are resolved or additional information regarding the IND is submitted.
Does a physician, in private practice, conducting research with an FDA regulated product, need to obtain IRB approval?
Yes. The FDA regulations require IRB review and approval of regulated clinical investigations, whether or not the study involves institutionalized subjects. FDA has included non-institutionalized subjects because it is inappropriate to apply a double standard for the protection of research subjects based on whether or not they are institutionalized. An investigator may be able to obtain IRB review by submitting the research proposal to a community hospital, a university/medical school, an independent IRB, a local or state government health agency or other organizations. If IRB review cannot be accomplished by one of these means, investigators may contact the FDA for assistance (Health Assessment Policy Staff, 301-827-1685).
Does a clinical investigation involving a marketed product require IRB review and approval?
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.
Is there a good website to learn more about INDs?
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:
Expanded Access IND
What is "expanded access" to investigational drugs?
Expanded access, sometimes called "compassionate use," “treatment use,” or a “single patient IND,” 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. More information about this can be found online.
Criteria for all expanded access uses:
- Patient(s) must have serious or immediately life-threatening disease/condition and no comparable or satisfactory alternative therapy.
- Potential benefit justifies potential risks, and potential risks are not unreasonable in the context of disease/condition.
- Access will not interfere with clinical investigations to support marketing approval of the expanded access use.
For the complete 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.
How do I prepare an expanded access IND submission?
Transferring an IND
What is the procedure to transfer INDs?
An IND sponsor can transfer responsibility for any or all of the IND sponsor obligations to a contract research organization or to another sponsor. Any such transfer shall be described in writing.
To transfer an IND to a new sponsor, the typical procedure is that the "old" sponsor submits an IND amendment to the FDA stating the transfer of the IND sponsorship and outlining the obligations to be transferred. The "new" sponsor also submits an amendment to the FDA accepting the sponsorship and its obligations and informing the FDA about the contact information of the new sponsor.
If not all obligations are transferred, such as the clinical monitoring function, for example, a description of each of the obligations being assumed by the contract research organization or the new sponsor is required in the submission. 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.
A sample IND Transfer Letter and information on how to complete the Form 1571 can be obtained from the Regulatory Affairs office.
Contents of an IND Application
What are the contents of an IND submission?
A sponsor must submit information for the IND in the following order:
- Cover sheet (Form FDA-1571)
- Table of Contents
- Introductory Statement and General Investigational Plan
- [(Reserved) — Previously, the FDA separated the Introductory Statement from the General Investigational Plan Since they are combined currently, this section is left "blank".]
- Investigator's Brochure (not needed for investigator-sponsored single-site studies)
- Chemistry, Manufacturing and Control Information (may not be needed for studies utilizing an approved drug)
- Pharmacology and Toxicology Information
- Previous Human Experience
- Additional Information
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.
The sponsor must submit three copies (one original and two copies) of all submissions to the IND file.
Each submission relating to an IND must be numbered sequentially using a four-digit serial number. The original 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.
What is Form FDA 1571?
What is Form FDA 1572?
Form 1572 is an FDA form that contains information about the investigator of the study. Investigators may participate in an investigation only after they provide the sponsor with a completed, signed Form 1572. It is your responsibility as a clinical investigator to include all sub-investigators who will be assisting you in the Form 1572.
What is Form FDA 3674?
Form 3674 is a certification of compliance that all applicable requirements of 42 USC § 282(j) have been met. At the time of submission of an Investigational New Drug application, the application must be accompanied by this certification. Where available, such certification must include the appropriate National Clinical Trial (NCT) numbers. The form and instructions can be found online.
Many trials are registered in Clinicaltrials.gov and CTRP by Clinical Research Support. Additional information on registering your clinical trials is available on the Clinicaltrials.gov Protocol Registration website.
What is Form 3500A?
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.
cGMP and Chemistry, Manufacturing and Controls Information
What is cGMP? Is it applicable to my trial?
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.
I am planning to initiate a Phase I clinical study with an investigational drug/biologic. Is the study subject to all cGMP requirements?
It depends. Some investigational drug/biologics used in a Phase 1 study are exempt from the cGMP requirements as specified in 21CFR 211. These investigational agents need to follow the requirements described in the following guidance document.
Does cGMP apply to products manufactured at Fred Hutch?
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.
IND Sponsor and Investigator Functions/Responsibilities
What is an IND "sponsor" and what are his/her responsibilities?
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 (21 CFR 312.50-59).
Sponsors are primarily responsible for:
- Selecting qualified investigators and providing them with the information they need to conduct an investigation properly;
- 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;
- maintaining an effective IND with respect to the investigations; and
- 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.
What is an "investigator" and what are his/her responsibilities?
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 (21 CFR 312.60-70).
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. for obtaining the informed consent of each human subject to whom the drug is administered.
FDA has issued an important Guidance for Industry that further describes investigator responsibilities. More detailed information is also listed in the ICH Good Clinical Practice (GCP) guidance document (Section 4).
How long is an investigator required to retain records?
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.
What are the common "mistakes" made by investigators?
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.
My study involves both Fred Hutch and UW facilities. Do I need to obtain IRB clearance from both organizations?
If you are a member of the University of Washington/Fred Hutch Cancer Consortium, you receive IRB review and approval from the Cancer Consortium IRB (CC-IRB). This committee is organized by Fred Hutch, but maintained for Cancer Consortium members and their studies only. If your primary appointment is with UW, you must obtain authorization via the UW Human Subjects Division’s Zipline system for submission to the CC-IRB.
If you are a Fred Hutch PI only, you receive IRB review and approval from Fred Hutch's IRB.
If you are a UW PI only, you receive IRB review and approval from the UW's Human Subjects Division.
Can I start patient-screening before a prospective patient's participation in a clinical study?
Informed consent must be obtained prior to initiation of any screening procedures that are performed solely for the purpose of determining eligibility for research. Clinical screening procedures for research eligibility are considered part of subject selection and recruitment process, and, therefore, require IRB oversight.
IND Amendments and Safety Reports
What are the types of IND amendments?
There are three major types of IND amendments: (a) Protocol amendments, (b) Information amendments, and (c) IND Safety reports.
A protocol amendment is filed 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
Safety reports are submitted to FDA when:
- An adverse event occurs that is serious, causally associated with the use of the drug/biologic, and unexpected; or
- There is a finding in laboratory animals or in vitro testing that suggests a significant risk to human subjects; or
- Clinical, epidemiological, or pooled analysis of multiple studies suggest a significant risk to human subjects
What is a serious adverse event (SAE)?
A serious adverse event is any adverse experience that results in:
- 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.
What are the regulations regarding reporting a serious adverse event? How do I know if the SAE is reportable?
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. FDA subsequently released a draft guidance with further recommendations in December 2015 and hosted a webinar on this topic shortly thereafter.
An adverse event is reportable 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”).
The final rule expects that the sponsor and investigators will first determine whether an adverse event is causally linked to the investigational drug/biologic. This determination can be made from a single event or from an aggregate analysis of a series of occurrences.
Serious adverse event reports must be made 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.
IND Annual Reports
What is an annual report? When is it due?
An annual report is a summary of the progress of the clinical investigation and information obtained during the previous year's clinical and non-clinical investigations. A sponsor shall submit the annual report within 60 days of the anniversary date that the IND went into effect. For example, if an IND was submitted on February 17, 2005, and FDA did not have any comments or questions, then the IND went into effect on March 17, 2005 (after the 30-day waiting period). Thus, the annual report is due on or before May 17, 2006. The annual report is due on or before the same day of each subsequent year.
The format and content of the annual report is described in 21 CFR 312.33.
Medical Devices and Investigational Device Exemptions (IDE)
What is a medical device?
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.
How are medical devices regulated?
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 800-1299. 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.
If I want to conduct a clinical trial on an experimental medical device, what do I need to do?
Many clinical trials on medical devices are conducted under Investigational Device Exemptions (IDE), which are described under 21 CFR 812. Certain trials may be exempt from these regulations. Clinical trials using a device that is deemed by the reviewing IRB not to represent a “significant risk” are conducted under IND regulations but may not require an IDE submission to FDA (“abbreviated requirements” under 21 CFR 812.2).
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.
What are the procedures to submit an IDE application?
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.
The IDE application is submitted in triplicate and is addressed to:
Food and Drug Administration
Center for Devices and Radiological Health
Document Mail Center - WO66-G609
10903 New Hampshire Avenue
Silver Spring, Maryland 20993-0002
The outside wrapper of each submission should be clearly marked indicating the content of the package (e.g., "IDE application," "Supplemental IDE application," etc).
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 very useful website for medical devices is "Device Advice"
General and Miscellaneous Questions
What are guidance documents? Do I need to follow them?
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 guidances in 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."
What are drug master files?
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.