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Operations Manual - Studies Regulated by the FDA and Use of Investigational Articles

Operations Manual - Part 8

[Operations Manual Table of Contents]

I. INTRODUCTION

The United States Food and Drug Administration (FDA) enforces the Food, Drug, and Cosmetic Act (FD&C Act) and other laws and regulations governing the use of drugs, biologics, and devices both in research studies and for treatment.

The FD&C Act generally prohibits the manufacture, delivery, use, receipt, or sale of any drug, biologic, or device that is “adulterated” or “misbranded”. New drugs, biologics, and devices that are not yet FDA-approved, as well as those used for a purpose or in a manner not already approved by the FDA, may be considered either adulterated or misbranded, or both. 

The FDA has adopted regulations to implement the FD&C Act. FDA regulations for drugs are outlined in 21 CFR 312, devices are in 21 CFR 812 and biologics are in 21 CFR 600. FDA regulations for informed consent (21 CFR 50) and Institutional Review Boards (21 CFR 56) also apply. Reporting of adverse events and unanticipated problems related to research on FDA-regulated products is covered in IRB Standard Operating Procedures and IRBMED Guidance.

The following sections describe when or under what circumstances an Investigational New Drug (IND) application, or an Investigational Device Exemption (IDE) is needed (Sections II-VI) and describe the roles and responsibilities of the FDA, IRBs, sponsors and investigators with respect to protocols involving investigational articles (Sections VII and VIII).

FDA regulations at 21 CFR 312 and 21 CFR 812, define “sponsor” and “sponsor-investigator,” as follows:

  • A sponsor is an organization or individual that initiates and takes responsibility for a clinical trial or other FDA-regulated project involving a drug, biologic or device.
  • A sponsor-investigator is an individual who both initiates and conducts an investigation of an FDA-regulated drug, biologic or device and under whose immediate direction the drug, biologic or device is administered or dispensed. The term does not include any person other than an individual. 

II. RESEARCH INVOLVING INDs OR IDEs

INDs and IDEs are the mechanism by which the FDA grants investigators special permission to conduct research using (1) a new (not yet FDA-approved) drug, biologic, or device, or (2) an FDA-approved drug, biologic, or device for a purpose or in a manner not already approved or cleared for use by the FDA.

Principal Investigators (PIs) are responsible for determining whether research in which they are engaged requires an IND or IDE and, if so, for securing the necessary FDA permissions and IRB approvals. An investigator who holds an IND or IDE is considered an FDA “sponsor” and must meet FDA sponsor requirements described in Section VII of this part. An investigator who is unsure whether an IND or IDE is required for a proposed research project should consult with the Medical School Institutional Review Board (IRBMED), the Michigan Institute for Clinical and Health Research Investigator IND/IDE Assistance Program (MICHR MIAP), the University of Michigan (U-M) Research Pharmacy and/or the Office of General Counsel (OGC). Guidance aids available on the IRBMED website summarize the circumstances under which an IND or IDE may be required.

Investigators who fail to obtain an IND or IDE when required by FDA regulations may be subject to civil and even criminal sanctions.

A. IND Requirements for Research Involving an Investigational Drug or Biologic

An IND is the FDA regulatory mechanism that allows a sponsor to ship an unapproved investigational drug or biologic to study sites and initiate clinical research on the drug.  IND regulations are outlined in 21 CFR 312.

An IND application is required for testing the safety and/or the effectiveness of:

  • Unapproved drugs or biologics;
  • Approved drugs or biologics for new intended uses, or studies that involve a route of administration or dosage level or use in a patient population that significantly increases the risks associated with the use of the drug product.

Human research involving unapproved drugs and biologics or FDA-approved drugs and biologics for new intended uses may proceed only under an IND that is approved by the FDA before the research begins. The FDA assigns an IND number and allows the investigation to begin after it determines that research participants will not be exposed to unreasonable risk.

1. Exemptions from IND Requirements

Certain investigations may be exempt from the requirement for an IND, if specified criteria are met. FDA exemption criteria are described in 21 CFR 312.2(b)(1). Investigations that are exempt from IND regulations still require IRB review and approval.  

Additionally, a limited number of specific types of clinical investigations (e.g., involving in vitro diagnostic biologicals such as blood grouping serum, reagent red blood cells, and anti-human globulin) conducted under certain conditions are also exempt from the IND requirement. See 21 CFR 312.2(b)(2)-(6).

Separate rules for bioavailability studies are described at 21 CFR 320.31

2. FDA Guidance Regarding IND Requirements and Exemptions

B. IDE Requirements for Research Involving Investigational Devices

Medical devices range from simple products such as bandages and tongue depressors to complex products such as cardiac pacemakers, surgical lasers, orthopedic implants, and imaging systems and software. Medical devices also include diagnostic products such as pregnancy test kits. Medical devices are intended to diagnose, cure, mitigate, treat or prevent disease by affecting the structure or function of the human body and are considered investigational when the device is the object of the study. Investigational devices are ones not yet cleared for use by the FDA or devices being used for an indication different than in the FDA approved labeling. When medical device research involves in vitro diagnostics and unidentified tissue specimens, the FDA defines the unidentified tissue specimens as human subjects.

An IDE is the FDA regulatory mechanism which permits an investigational device to be shipped lawfully for the purpose of conducting investigations of that device. IDE requirements are outlined in 21 CFR 812. The FDA assigns an IDE number to a significant risk device and allows the investigation to begin after it determines that research participants will not be exposed to unreasonable risk.

IDE regulations require research investigations to test the safety and/or the effectiveness of the following investigational devices:

  • Unapproved devices
  • Approved devices for new indications

1. Level of FDA Oversight

The level of FDA oversight of research varies according to the level of risk (significant or non-significant) to research participants posed by the device. IDE regulations, 21 CFR 812, describe three types of device studies:

  • Significant Risk Device Studies
  • Non-Significant Risk Device Studies
  • IDE Exempt Studies

Investigators who are studying devices must provide the IRB with complete and accurate information about the regulatory status and risk level of each device.

a. Significant Risk (SR)/Non-significant Risk (NSR) Determinations

A significant risk (SR) device is a device that presents a potential for serious risk to the health, safety, or welfare of a subject, and is one of the following:

  • Is intended as an implant;
  • Is for use in supporting or sustaining human life;
  • Is for a use of substantial importance in diagnosing, curing, mitigating, or treating disease, or otherwise preventing impairment of human health; or
  • Otherwise presents a potential for serious risk to the health, safety, or welfare of a subject.

Significant risk device studies are subject to all of the requirements of 21 CFR Part 812. An IDE application must be approved by the FDA and have IRB approval before the study can begin.

b. Non-Significant Risk Device Studies

A non-significant risk (NSR) device is an investigational device that does not meet the definition of a significant risk device.

A NSR study does not require submission of an IDE application to FDA. Instead, the sponsor must conduct the study as required by “abbreviated” IDE requirements, which address, among other items, requirements for IRB approval and informed consent, record keeping, labeling, promotion, and study monitoring. See 21 CFR 812.2(b). Unless the sponsor is notified otherwise by the FDA, an NSR study is considered to have an approved IDE if the sponsor fulfills these abbreviated requirements, and the study may begin immediately following final IRB approval.

c. Significant Risk/Non-Significant Risk (SR/NSR) Determination

The SR/NSR determination is made initially by the FDA-recognized sponsor (or sponsor-investigator) but must be confirmed by an IRB.  IRBs do not have to make the SR or NSR determination if FDA has already made the risk determination.  An FDA guidance document helps sponsors, investigators and IRBs distinguish significant from non-significant risk studies. See Significant Risk and Non-Significant Risk Medical Device Studies.

2. Sponsor’s Role

If the sponsor believes the study is NSR, the sponsor provides the reviewing IRB with an explanation of its determination and any other information that may assist the IRB in evaluating the risk of the study. This includes, at a minimum, the following information:

  • A description of the device;
  • Reports of prior investigations with the device;
  • The proposed investigational plan;
  • A description of patient selection criteria;
  • A description of monitoring procedures;
  • FDA’s assessment of the device study’s risk, if one has been made; 
  • Whether other IRBs have reviewed the proposed study;
  • Any other information that the IRB deems necessary to make its decision.

3. IRB’s Role

The IRB may agree or disagree with the sponsor’s initial assessment. If the IRB agrees with a NSR assessment and approves the study, the study may begin without submission of an IDE application to FDA. If the IRB disagrees, the sponsor must notify FDA within five days that a SR determination has been made. The study can be conducted as an SR investigation following FDA approval of an IDE application.

The IRB’s SR/NSR determination must be based on the proposed use of the device in an investigation and not on the device alone. In making its determination, the IRB must consider the nature of the harm that may result from use of the device. If the harm could be life-threatening, result in permanent impairment, or necessitate medical or surgical intervention to preclude permanent impairment, the study must be treated as SR. If the subject must undergo a procedure as part of the study (e.g., surgery), the IRB must consider the potential harm that could be caused by the procedure in addition to the potential harm that could be caused by the device. In making its SR/NSR determination, the IRB may consult directly with the FDA for its opinion.

4. FDA’s Role

The FDA has the ultimate authority to determine whether a device study is SR or NSR. In the event that the FDA becomes aware of, and disagrees with, an IRB’s NSR determination, an IDE application must be submitted to FDA. If the FDA does not act within 30 days of its confirmed receipt of the IDE application, the study may proceed. Conversely, if a sponsor files an IDE with FDA because the study is presumed to be SR, but the FDA classifies the study as NSR, the FDA will return the IDE application to the sponsor and the study may be presented to IRB(s) as a NSR investigation.

Once a final SR/NSR decision is made by the IRB (or the FDA), the IRB must consider whether the study should be approved, using the same criteria it would use in reviewing any other research involving FDA-regulated products.

5. Device Studies Exempt from IDE Requirements

Certain investigations may be exempt from the requirement for an IDE, if specified criteria are met. FDA exemption criteria are described in 21 CFR 812.2(c). Investigations that are exempt from IDE regulations still require IRB review and approval. Separate rules for studies of in vitro diagnostic devices are described at 21 CFR 809 subpart H.

Additional guidance regarding IDE requirements and exemptions is available at: Device Advice:  Investigational Device Exemption (IDE).

C. Off-Label Use of an FDA-Approved Drug, Biologic or Device

“Off-Label use” means the use of legally marketed and/or FDA-approved drugs, biologics and devices for a purpose or in a manner not already approved by the FDA. Whether an IND or IDE is required for off-label use depends on whether the use is for clinical treatment or for research.

1. “Off-label” use for clinical treatment of individual patients

Good medical practice and the best interests of the patient require that health care providers use legally available drugs, biologics, and devices according to their best knowledge and judgment, regardless of FDA-approved indications and labeling. A treating clinician therefore may use a legally marketed product for a purpose other than that approved by the FDA (i.e., off-label), but in doing so must be well informed about the product, must base its use on firm scientific rationale and sound medical evidence, and must maintain records of the product’s use and effects. Use of a marketed product in this manner, when the intent is the “practice of medicine” (i.e., diagnosis, cure, mitigation, treatment, or prevention of disease in humans), does not require the submission of an IND or IDE or review by an IRB.

2. “Off-label” use for research

If the off-label use of an FDA-approved product is used to collect data about the product’s safety or efficacy, or for other non-diagnostic or non-therapeutic purposes, an IND or IDE is generally required if human subjects are involved. It is useful to consult with the IRB to determine when data collection for off-label use may be considered research.

FDA guidance for treating clinicians on off-label use is available at:  "Off-Label" and Investigational Use of Marketed Drugs, Biologics, and Medical Devices - Information Sheet: Guidance for Institutional Review Boards and Clinical Investigators.

III. EXPANDED ACCESS TO INVESTIGATIONAL DRUGS, BIOLOGICS AND DEVICES

The FDA has developed special mechanisms to expand access to promising investigational drugs, biologics, and devices (“investigational articles”) for clinical treatment of patients without compromising the protection of human subjects or the thoroughness and scientific integrity of product development and marketing approval. Collectively, these mechanisms are known as “expanded access”. 

A. Expanded Access as Research and Clinical Treatment

Although an investigational article used under the FDA expanded access mechanism is intended for the purpose of clinical treatment, the FDA may consider the treatment to constitute a “clinical investigation” (i.e., research), and require that data from the treatment be reportable in a marketing application.  Conversely, under the U.S. Department of Health and Human Services (HHS) human research protection rules, patients who receive investigational articles through the expanded access mechanism are not considered research subjects, and outcomes of expanded access treatments may be included in reports of research funded by federal agencies that follow HHS rules.

If the FDA considers the treatment under the expanded access mechanism to constitute “clinical treatment,” an FDA accepted/approved IND or IDE submission or an amendment to an already existing IND or IDE is required prior to initiation of the clinical treatment. 

Once submitted, an expanded access IND or IDE goes into effect 30 days after the FDA receives the IND or IDE submission, unless the FDA notifies the sponsor otherwise during that 30-day period. In many cases, the IND or IDE will go into effect earlier, as soon as the FDA notifies the sponsor that treatment use may begin.

B. IRB’s Role

In addition to an FDA-approved IND or IDE, most expanded access requests must be approved at a convened meeting of an IRB prior to administration of the treatment, and an IRB-approved informed consent form must be used to provide pertinent information to the patient and document his or her consent. The ONLY exception to this requirement is for individual patient emergency use, described more fully in Section IV, below

C. Clinician Responsibilities

Any clinician providing treatment under an expanded access IND or IDE has particular additional responsibilities and obligations to the IRB and the FDA, if functioning as the FDA sponsor, and may have additional responsibilities to the company providing the investigational article. These include:

  • Submission of adverse event reports to the IRB and to the FDA, if functioning as the study sponsor. Adverse events are submitted to the FDA sponsor if someone other than the treating clinician is the sponsor and by contractual agreement with a company providing the investigational test article;
  • Annual reports to the FDA, if serving as the FDA sponsor; and
  • Withdrawal of the IND or IDE with the FDA at the conclusion of the treatment period, if serving as the FDA sponsor.

The IRB also requests submission of annual and termination reports.

D. Expanded Access to Investigational Drugs and Biologics for Treatment Use

Investigational drugs and biologics are sometimes used for treatment of serious or life threatening conditions either for a single subject or for a group of subjects. The procedures that have evolved for an investigational new drug or biologic (IND) used for these purposes reflect the recognition by the FDA that, when no satisfactory alternative treatment exists, patients are generally willing to accept greater risks from drugs and biologics that may treat life threatening and debilitating illnesses. 

The expanded access IND regulations are categorized into three levels depending on the expected numbers of subjects to be treated and include: 

  • Expanded access for individual patients in emergency and non-emergency situations (21 CFR 312.310);
  • Expanded access for intermediate-size patient population (21 CFR 312.315); and
  • Expanded access for large patient population under a treatment IND.

The regulations also describe criteria that must be met to authorize expanded access, list requirements for expanded access submissions, and describe safeguards that will protect patients and preserve the ability to develop meaningful data about the use of the drug. FDA guidance on expanded access INDs is available here:

Other mechanisms used by the FDA for expanded access to investigational drugs and biologics are listed below.

1. Open Label Protocols or Open Label IND

These are usually uncontrolled Phase 3 trials, carried out to obtain additional safety data. They typically are used when the controlled trial has ended and treatment is continued so that the subjects in both the interventional and control groups may receive the benefits of the investigational drug while marketing approval is being obtained. These trials require prior IRB review and approval and informed consent of subjects.

2. Group C Treatment IND

“Group C” is a special class of Treatment IND that has been established by the FDA and the National Cancer Institute (NCI) for the distribution of certain promising investigational agents (generally Phase 3 study drugs) to oncologists for the treatment of cancer under protocols outside the controlled clinical trial.  Group C drugs are distributed only by the National Institutes of Health (NIH) under NCI protocols. 

Because administration of Group C drugs is not done with research intent, the FDA has generally granted a waiver from the IRB review requirements (21 CFR 56.105). Even though FDA has granted a waiver for these drugs, an IRB may still choose to conduct a review under its policies and procedures. 

3. Parallel Track Policy

The FDA’s “Parallel Track” policy facilitates early access to promising new drugs for AIDS/HIV related diseases under a separate expanded access protocol that “parallels” the controlled clinical trials that are essential to establish the safety and effectiveness of new drugs. These studies require prospective IRB review and informed consent.

E. Expanded Access to Investigational Devices

An unapproved medical device may normally only be used on human subjects through an approved clinical study in which the subjects meet certain criteria and the device is only used in accordance with the approved protocol by a clinical investigator participating in the clinical trial. However, there may be circumstances under which a health care provider may wish to use an unapproved device to save the life of a patient or to help a patient suffering from a serious disease or condition for which no other alternative therapy exists. Patients/physicians faced with these circumstances may have access to investigational devices under one of five main mechanisms by which FDA may make an unapproved device available:

  • Compassionate Use (or Single Patient/Small Group Access);
  • Treatment Use;
  • Continued Access;
  • Emergency Use (see Section IV, below);
  • Emergency Research (see Section V, below)

These mechanisms can be used during a certain timeframe in the IDE process if the criteria are met. FDA approval is required except in the case of emergency use. The mechanisms are summarized below.

1. Compassionate Use (devices)

The FDA “compassionate use” provision is intended to provide non-emergency access to an investigational device by an individual or small numbers of patients who the treating clinician believes will benefit from use of the device.

Additional requirements for compassionate use of devices are available from the FDA in: IDE Early/Expanded Access - Compassionate Use (or Single Patient/Small Group Access).

2. Treatment Use (devices)

A Treatment IDE provides a mechanism for a device that is not yet FDA approved to be used to treat a serious or immediately life-threatening disease or condition in patients for whom no comparable or satisfactory alternative device or other therapy is available. The treatment use provision of the IDE facilitates the availability of promising new devices to desperately ill patients as early in the device development process as possible. In the case of a serious disease, a device may be made available for treatment use after all clinical trials have been completed. In the case of an immediately life-threatening disease, a device may be made available for treatment use prior to the completion of all clinical trials.  See IDE Early/Expanded Access - Treatment Use from the FDA.

3. Continued Access (devices)

FDA may allow continued enrollment of subjects after a controlled clinical trial under an IDE has been completed.  This permits access to the investigational device while a marketing application is being prepared by the sponsor or reviewed by the FDA and facilitates the collection of additional safety and effectiveness data to support the marketing application or to address new questions regarding the investigational device. This is referred to as an “extended investigation.” A request for an extended investigation must be submitted by the sponsor of the IDE in writing as a supplement to the IDE.

Additional information about the requirements for a Continued Access IDE application is available here:

IV. Emergency Use of Investigational Articles

Emergency use is defined as the use of an investigational drug, biologic or device (i.e. investigational article) with a human subject in a life-threatening situation in which no standard acceptable treatment is available and in which there is not sufficient time to obtain IRB approval (21 CFR 56.102(d)). The emergency use provisions in the FDA regulations, 21 CFR 56.104(c), provide an exemption from prior review and approval by the IRB as long as the emergency use is reported to the IRB within five working days.

Life-threatening, for the purposes of section 56.102(d), includes both life-threatening and severely debilitating, as defined below:

  • Life-threatening means diseases or conditions where the likelihood of death is high unless the course of the disease is interrupted and diseases or conditions with potentially fatal outcomes where the end point of clinical trial analysis is survival. 
  • Severely debilitating means diseases or conditions that cause major irreversible morbidity. Examples of severely debilitating conditions include blindness, loss of arm, leg, hand or foot, loss of hearing, paralysis or stroke.

A. IRB Review

Prospective IRB review is required unless the conditions for the emergency use exemption from prior review and approval by the IRB are met (21 CFR 56.104(c) and 56.102(d)).

The FDA regulations do not provide for expedited IRB approval in emergency situations; full board approval of the report of the emergency use to the IRB is required. See http://www.fda.gov/RegulatoryInformation/Guidances/ucm126491.htm.

B. Single Use

The exemption, which may not be used unless all of the conditions described in 21 CFR 56.102(d) exist, allows for one emergency use of a test article without prospective IRB review. FDA regulations require that any subsequent use of the investigational product at the institution have prospective IRB review and approval. FDA acknowledges, however, that it would be inappropriate to deny emergency treatment to a second individual if the only obstacle is that the IRB has not had sufficient time to convene a meeting to review the issue.

C. Informed Consent

Even for an emergency use, a treating clinician is required to obtain informed consent from the subject or the subject's legally authorized representative unless both the treating clinician and a physician who is not otherwise participating in the clinical investigation certify in writing all of the following (21 CFR 50.23):

  • The subject is confronted by a life-threatening situation necessitating the use of the device;
  • Informed consent cannot be obtained because of an inability to communicate with, or obtain legally effective consent from, the subject;
  • Time is not sufficient to obtain consent from the subject's legal representative; and 
  • No alternative method of approved or generally recognized therapy is available that provides an equal or greater likelihood of saving the subject's life.

If, in the treating clinician’s opinion, immediate use of the investigational drug or biologic is required to preserve the subject's life, and if time is not sufficient to obtain an independent physician's determination that the four conditions above apply, the treating clinician should make the determination and, within five working days after the use of the drug or biologic, have the determination reviewed and evaluated in writing by a physician who is not participating in the clinical investigation. The treating clinician must notify the IRB within five working days after the use of the drug, biologic or device (21 CFR 50.23(c)).

D. Additional Guidance

Treating clinicians who seek to use an investigational article under the FDA emergency use provision are advised to consult IRBMED Guidance on this topic. Treating clinicians may also obtain advice from MICHR MIAP, the U-M Research Pharmacy and/or the Office of General Counsel.

E. Emergency Use of Investigational Drugs and Biologics

Emergency use of an investigational drug or biologic generally requires an IND.  If the intended subject does not meet the criteria of an existing study protocol, or if an approved study protocol does not exist, the usual procedure is to contact the manufacturer and determine if the drug or biologic can be made available for the emergency use under the company's IND.

However, the need for an investigational drug may arise in an emergency situation that does not allow time for submission of an IND in the usual manner. In an emergency situation, the request to use the drug may be made via telephone or other rapid means of communication. The FDA must issue an emergency IND that allows authorization to ship and allows expanded access clinical treatment to begin. The IND that authorizes treatment to begin may be provided by an FDA official over the telephone. Such authorization requires the sponsor to file an IND application within 15 days of the date FDA authorized the emergency use. In these situations, shipment of and treatment with the drug may begin prior to FDA’s receipt of the written IND submission that is to follow the initial request (21 CFR 312.310).

1. Clinician Responsibilities

In the event that a treating clinician seeks to use an investigational drug or biologic to treat a life-threatening or severely debilitating condition under emergent circumstances, the following steps are generally required:

  • Contact the manufacturer of the investigational drug or biologic to determine if they will make the drug or biologic available for emergency use and whether they will hold the IND.
  • If an IND for the use already exists, notify the FDA-recognized sponsor (i.e., IND holder) of the emergency use.
  • If an IND does not exist, or is not available for the emergency use under the existing IND, time permitting, obtain an independent assessment by an uninvolved physician.
  • Obtain informed consent from the patient or legally authorized representative, if possible. See IRBMED emergency use informed consent template.
  • Notify the IRB of use as soon as possible (prior to initiating treatment, if possible, or within five working days of the use).

After the emergency, the treating clinician must:

  • Report the emergency use to the IRB (by eResearch Emergency Use application) within five days and otherwise comply with IRB requirements.
  • Obtain an independent assessment by an uninvolved physician within five days of the use, if consent could not be obtained from the patient or legally authorized representative prior to the use.
  • Evaluate the likelihood of a similar need occurring again and, if future use is likely, immediately initiate efforts to obtain IRB approval and an approved IND for subsequent use.  NOTE:  FDA acknowledges, however, that it would be inappropriate to deny emergency treatment to a second individual if the only obstacle is that the IRB has not had sufficient time to convene a meeting to review the issue.
  • If holding the IND, provide the FDA, within 15 days of emergency use, a written summary of the conditions constituting the emergency, subject protection measures and results; otherwise, provide the summary to the IND holder.
  • If an IND has been submitted and disapproved by FDA, the investigational article may not be used even in an emergency.
  • If the treating clinician is the FDA sponsor and holds the IND, once administration of the test article is complete, submit a final report to FDA and withdraw the IND.

2. FDA Guidance on Emergency Use of an Investigational Drug or Biologic 

F. Emergency Use of Investigational Device

In general, an unapproved medical device may be used only on human subjects when the device is under clinical investigation and when used by investigators participating in a clinical trial. However, the FDA recognizes that there may be circumstances under which a health care provider may wish to use an unapproved device to save the life of a patient with an, or to prevent, irreversible morbidity when no other alternative therapy exists.

Emergency use of an unapproved device may occur when: (i) an IDE for the device does not exist, (ii) when a treating clinician wants to use the device in a way not approved under the IDE, or (iii) when a treating clinician is not an investigator under the IDE. In each situation, emergency use of an unapproved device may occur without prior approval from the FDA or an IRB. 

1. Clinician Responsibilities

If a treating clinician intends to treat a patient with an unapproved medical device in an emergency situation, the FDA expects the treating clinician to:

  1. Determine that:
    • The patient has a life-threatening condition that needs immediate treatment (including serious diseases or conditions such as sight-threatening and limb-threatening conditions as well as other situations involving risk of irreversible morbidity);
    • No generally acceptable alternative treatment for the condition exists; and
    • Because of the immediate need to use the device, there is no time to use existing procedures to get FDA approval for the use;
  2. Assess the potential for benefit from the use of the unapproved device;
  3. Have substantial reason to believe that benefits will exist.

In the event that a device is used in circumstances meeting the criteria listed above, the treating clinician should follow as many patient protection procedures as possible. Such patient protection procedures include obtaining:

  • Informed consent from the patient or a legal representative;
  • Clearance from the institution as specified by their policies;
  • Concurrence of the IRB chairperson;
  • An independent assessment from an uninvolved physician prior to, or after, use, as appropriate to the situation, if informed consent cannot be obtained; and
  • Authorization from the IDE sponsor, if an approved IDE exists for the device.

After the emergency use occurs, the treating physician is responsible for ensuring that certain follow-up procedures occur:

  • As soon as possible and no later than five working days of the use, report the emergency use to the IRB in an eResearch Emergency Use application.
  • Obtain an independent assessment by an uninvolved physician within five days of the use, if consent could not be obtained from the patient or legally authorized representative prior to the use.
  • Evaluate the likelihood of a similar need occurring again and, if future use is likely, immediately initiate efforts to obtain IRB approval and an approved IDE for subsequent use. NOTE:  FDA acknowledges, however, that it would be inappropriate to deny emergency treatment to a second individual if the only obstacle is that the IRB has not had sufficient time to convene a meeting to review the issue.
  • If an IDE exists for the device, within five working days of the use, the treating clinician should provide the IDE sponsor with sufficient patient follow-up information to allow the sponsor to comply with the reporting requirements of the IDE regulation.  The sponsor must report the use to the FDA via a supplement within five working days from the time the sponsor learns of the use. The supplement should contain a summary of the conditions constituting the emergency, the patient protection measures that were followed (as discussed below), and patient outcome information.
  • If no IDE exists, within five working days of the use, the physician should submit a follow-up report on the use of the device to the FDA, including a summary of the conditions constituting the emergency, patient protection measures that were followed, and patient outcome information.

2. FDA Guidance on Emergency Use of Investigational Devices

V. Planned Emergency Research Using Investigational Articles

Planned emergency research is a rarely used, but important, type of research that allows participants to be enrolled without prior informed consent. It differs from emergency use of a test article described above and has additional, specific requirements for investigators and the IRB (21CFR 50.24).

Investigators who wish to conduct planned emergency research should consult with IRB staff prior to submission of the protocol to the IRB.  

For more information about planned emergency research using an investigational article. See IDE Early/Expanded Access:  Emergency Research.

VI. Humanitarian Use Devices (HUD) and Humanitarian Use Exemptions (HDE)

A FDA-designated Humanitarian Use Device (HUD) is intended to benefit small populations (<4,000 individuals) with a rare condition for which effectiveness cannot be readily determined prior to marketing. Before the treating clinician may use a HUD, the FDA-recognized sponsor must obtain a Humanitarian Use Exemption (HDE). The treating clinician must also obtain IRB approval (via full board approval), unless the use of the HUD meets criteria for emergency use.  Informed consent documents must not refer to the humanitarian use of the device as “research”.

Additional information about HUDs and HDEs is available here:  

VII. FDA Sponsors and Sponsor-Investigators

FDA regulations at 21 CFR 312 and 21 CFR 812, define “sponsor” and “sponsor-investigator,” as follows:

  • A “sponsor” is an organization or individual that initiates and takes responsibility for a clinical trial or other FDA-regulated project involving a drug, biologic or device.
  • A “sponsor-investigator” is an individual who both initiates and conducts an investigation of an FDA-regulated drug, biologic or device and under whose immediate direction the drug, biologic or device is administered or dispensed. The term does not include any person other than an individual.

Part of an FDA sponsor’s or sponsor-investigator’s responsibility is to obtain any required IND or IDE from the FDA. For that reason, a “sponsor” is sometimes referred to as the IND or IDE “holder”.

A. University/University Employee as Sponsor/Holder 

The University, itself, generally does not “sponsor” (or “hold”) INDs or IDEs and a University faculty or staff member (“employee”) may not apply for an IND or IDE on behalf of the University without written approval of the Vice President for Research or his designee.

University employees may, however, act as “sponsors” or “sponsor-investigators” and hold their own INDs or IDEs if they: (1) have adequate training, experience, and support to properly conduct and monitor the relevant project activities, and (2) are able and willing to comply with relevant regulatory and institutional requirements.

B. Sponsor-Investigator Responsibilities

Investigators who initiate and submit IND or IDE applications to the FDA assume the responsibilities of both the investigator and the sponsor. The responsibilities of a sponsor are described at 21 CFR 312.50-312.59 and 812.40-812.47. Under FDA regulations, an academic sponsor or sponsor-investigator has the same obligations as a multi-national pharmaceutical manufacturer that sponsors or holds an IND or IDE. 

When a U-M employee applies to be the sponsor or sponsor-investigator of an IND or IDE, they make a personal commitment to the FDA to comply with a complex set of requirements (21 CFR 312, 812, and others) regarding the investigational article itself and the overall management of the project, as described below in Section VIII. In addition, any U-M employee serving or seeking to serve as the sponsor or sponsor-investigator of an IND or IDE in conjunction with his or her University appointment must also:

  • Complete an eResearch application for IRB approval indicating the intent to seek an IND or IDE prior to submission of an application to the FDA;
  • Participate in education delineating FDA Sponsor-Investigator requirements;
  • Consult with MICHR MIAP and consider using its services for document preparation assistance, application review, and maintenance of an active IND or IDE;
  • Archive all documents, including all FDA submissions, related to the IND or IDE in the eResearch IRB application.

C. Clinical Trials Registration

The holder of the IND or IDE (the IND or IDE “sponsor” or “sponsor-investigator”) for a clinical investigation is responsible for registering the trial on ClinicalTrials.gov prior to the enrollment of the first subject. The ClinicalTrials.gov website is maintained by the National Library of Medicine (NLM) at the National Institutes of Health (NIH). It is a resource that provides the public with information about clinical trials. When seeking informed consent from subjects, investigators must ensure that the informed consent document and process include a statement that the trial is registered with ClinicalTrials.gov, in accordance with the provisions of 21 CFR 50.25(c). This statement is part of the U-M IRBMED Informed Consent template. 

For additional information, see the Medical School guidance on clinical trial registration.

U-M IRBs overseeing research involving a sponsor or sponsor-investigator have standard operating procedures and/or guidance concerning sponsors, sponsor-investigators and their roles and responsibilities with regard to FDA-regulated research, INDs and IDEs.

D. Noncompliance

Serious or continuing noncompliance with the obligations of a sponsor or sponsor-investigator may lead to University restrictions on the ability of the faculty member to enter into future agreements with the FDA. See Part 12 of this OM.

FDA guidance for sponsor-investigators is available at:

E. Manufacturer of Investigational Articles

In the rare event that a U-M employee intends to manufacture an investigational article, advice must be sought from one or more the following U-M offices at the earliest opportunity and prior to use of the article with humans (even for feasibility assessment):  IRB, Office of the General Counsel, U-M Office of Research, UMMS Office of Regulatory Affairs. These offices will alert other offices as applicable, in order that the best University advice and support can be provided to the research team before and during the manufacturing process.

VIII. INVESTIGATOR and IRB Responsibilities for FDA-Regulated Research

A. Ensuring Review by Appropriate IRB

The investigator conducting FDA-regulated research must ensure that an appropriate University IRB (or other IRB with which U-M has established a reliance agreement) is responsible for the initial and continuing review of the research, in accordance with the FDA requirements at 21 CFR 50 and 56. The U-M IRBs are registered with both the FDA and the Office for Human Research Protections (OHRP). Changes may be made to a research protocol only after notifying the sponsor and receiving approval from the IRB, except when necessary to eliminate apparent immediate hazards to subjects. Informed consent must be obtained from all prospective subjects prior to enrollment in the research.

B. Verification of IND or IDE Acquisition Prior to Release of Final IRB Approval

Through the eResearch application for IRB approval, PIs answer a series of questions designed to determine whether or not an IND or IDE may be required for a research project. If it appears that an IND or IDE may be required, the reviewing IRB will require one of the following in order to verify IND or IDE acquisition prior to release of final IRB approval:

  • Written FDA documentation that an IND or IDE has been granted (including the IND or IDE number), or that an existing IND or  IDE has been amended, as appropriate, to cover the specific project in question; or
  • Written documentation that the FDA’s time for consideration of an IND or IDE application for the research project in question has lapsed without a notice of disapproval or conditional approval and without a request for additional information (the PI must still provide the IRB with FDA documentation of the IND or IDE number assigned by FDA when FDA acknowledged receipt of the IND or IDE application); or
  • Written documentation of the FDA’s determination that an IND or IDE is not required.

Alternatively, for research involving an investigational device, once the PI demonstrates to the IRB’s satisfaction that the research meets the FDA’s criteria for a non-significant risk (NSR) study, IRB approval of the research and documentation of its NSR decision is sufficient.

C. Oversight of FDA-Regulated Research

In addition to ensuring IRB review and approval, and in addition to general PI responsibilities outlined in Part 6 of this OM, a PI conducting FDA-regulated research must personally conduct or supervise the study as specified in the signed investigator statement, the investigational plan (protocol), any applicable sponsor agreement, and the IRB-approved application and associated materials. 

Before initiating a research project, the PI must read and understand the information in the investigator’s brochure or similar documentation, including the risks and potential benefits of the investigational article.

The PI is responsible for ensuring that all co-investigators and other research team members assisting in the conduct of the study are informed about their obligations and are adequately trained to carry out their responsibilities competently and appropriately. PI responsibilities are described in further detail at 21 CFR 312.60-312.69 (drugs and biologics); and 21 CFR 812.100-812.110 (devices).

See, also, FDA guidance on this topic at FDA IDE Responsibilities.

D. Investigational Article Accountability

During the research project, the PI is responsible for all aspects of protocol implementation, including proper receipt, storage and the documentation, security, use, and disposal of the investigational article (drug, biologic, or device). In the eResearch application for IRB approval, the PI must describe his or her plan to assure that investigational articles are used only in approved protocols and under the direction of approved investigators. Deviations from these plans are permitted only in emergency circumstances, consistent with FDA requirements and University policies on emergency use. An IRB may not approve a proposed research project that does not include satisfactory plans for investigational article accountability. Test article accountability procedures are described in more detail in Part 3, Section III.C.6.i of this OM.

E. Charging for Investigational Articles

When the FDA-recognized sponsor or sponsor-investigator intends to charge subjects for investigational articles or related treatment or services, he or she must comply with all IRB policies (e.g., to ensure that the charges are appropriate and equitable, and to require disclosure of the charges in the informed consent document and process), institutional billing policies, and professional ethics, as well as the FDA guidelines at: Charging for Investigational Products - Information Sheet. The charge may not exceed an amount that is necessary to recover the costs associated with the manufacture, research, development, and handling of the investigational article.

Draft FDA guidance on charging for investigational drugs and biologics is available here: Charging for Investigational Drugs Under an IND - Q&A.

F. Records and Documentation

The PI must ensure the creation and maintenance of complete and accurate research records, such as informed consent documentation, case report forms, correspondence files, and other relevant information for record keeping purposes and possible inspection by institutional officials, outside sponsors, and regulatory agencies.  

In addition, the names and commitment of study team members, as well as their responsibilities, qualifications, and study-specific training must be clearly documented, including, as appropriate, on FDA Form 1572 (drugs and biologics), investigator agreements (devices), and delegation logs.

1. Electronic Records

FDA regulations at 21 CFR Part 11 set forth the criteria under which the agency considers electronic records, electronic signatures and handwritten signatures executed to electronic records to be trustworthy, reliable, and generally equivalent to paper records and handwritten signatures executed on paper. Part 11 is intended to ensure that information submitted to and considered by the FDA is readily accessible and auditable in order to validate its accuracy.

The University has conducted and documented a self-assessment of eResearch compliance with 21 CFR Part 11 (Self Assessment of eResearch Compliance.pdf) and has issued an electronic signature certification statement (Certification of Electronic Signatures.pdf ). Similar documentation of Part 11 compliance of UMHS medical record systems is available at University and UMHS Policies and Materials Relating to Human Subjects Research.

2. Record Retention

The FDA requires that records be retained in compliance with applicable laws, regulations, policies, and agreements. The required manner and duration of record retention, as specified in these rules, may vary widely and may also depend on the characteristics of the particular research project or other related activity. PIs are also advised to consult with the relevant FDA-recognized sponsor before disposing of records associated with a particular research project or related activity. U-M institutional guidance on record retention is available at U-M Medical School Record Keeping Guidelines

G. Required Reporting

The PI must ensure that adverse events and other unanticipated problems involving risks to subjects or others are reported to the FDA sponsor and the IRB in a timely manner and be consistent with the IRB approved reporting plan in the study protocol. In addition, promptly after receipt, PIs must provide to the IRB copies of any audit or inspection reports, warning letters, debarment notices, or similar documents issued by sponsors, government regulators (such as the FDA or NIH), internal oversight units, or other organizations with oversight responsibilities.

More information on adverse event and other reporting requirements is available in IRB Standard Operating Procedures and in IRBMED Guidance.

H. ICH-E6 and GCP

The International Conference on Harmonisation’s (ICH) Efficacy Guideline (E6) on Good Clinical Practice (GCP) is an international standard established to promote the ethical and scientifically sound design, conduct, recording, and reporting of human clinical trials. When a research protocol or agreement specifies that ICH GCP will be followed, the FDA and U-M oversight authorities will enforce compliance with GCP requirements.

Additional information about GCP guidelines is available at: Guidance for Industry - E6 Good Clinical Practice: Consolidated Guidance.

I. FDA Inspections of FDA-Regulation Research and Related Activities

The FDA conducts routine and for-cause inspections of clinical trials, clinical investigators, and IRBs, in order to validate data that is under FDA consideration, verify protection of human subjects, confirm general compliance with FDA and other applicable regulations, policies, and agreements (including sponsor agreements), and investigate complaints and self-reports of non-compliance. FDA inspections are typically scheduled in advance, but may be conducted without advance notice.

When contacted by the FDA to schedule an inspection (or the FDA has arrived without advance notice), the PI or a member of the research team is expected to contact one of the following offices at the earliest opportunity:  IRB, Office of the General Counsel, U-M Office of Research, UMMS Office of Regulatory Affairs. Whichever office is reached will alert the other offices of the inspection, in order that the best University advice and support can be provided to the research team during the inspection process.