Research

Human Research Protection Program Policy and Procedure Manual - Section 7

7 Investigational Drugs & Devices in Research

7.1 Purpose

7.2 Definitions

7.3 FDA Exemptions

7.4 IND/IDE Requirements

7.5 Responsibilities

7.5.1.1 Investigator

7.5.1.2 IRB

7.6 Emergency Use

7.6.1 Emergency Exemption from Prospective IRB Approval

7.6.2 Emergency Waiver of Informed Consent

7.6.3 Treatment IND

7.6.4 Emergency Waiver of IND

7.7 Waiver of Informed Consent for Planned Emergency Research

7.8 Humanitarian Use Devices (HUD)

 

7.1 Purpose

The following procedures describe the use of investigational drugs and devices in research under the auspices of Brown University.  Use of investigational drugs must be conducted according to FDA IND regulations, 21CFR Part 312, and other applicable FDA regulations. Use of an investigational device in a clinical trial to obtain safety and effectiveness data must be conducted according to FDA’s IDE regulations, 21CFR Part 812, and other applicable FDA regulations.

 

7.2 Definitions

Investigational Drug. An investigational drug for clinical research use is one for which the PI or a sponsor has filed an IND application (21CFR Part 312) or an approved drug that is being studied for an unapproved or approved use in a controlled, randomized, or blinded clinical trial.

 

Investigational Device. is a medical device that is the subject of a clinical study designed to evaluate the effectiveness and/or safety of the device. As further stated, a device is any healthcare product that does not achieve its primary intended purpose by chemical action or by being metabolized.

 

IND. IND means an investigational new drug application in accordance with 21CFR Part 312.

 

IDE.  IDE means an investigational device exemption in accordance with 21CFR 812.

 

Emergency Use.  Emergency use is defined as the use of an investigational drug or biological product with a human participant 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.

 

Significant Risk (SR). Significant risk device means an investigational device that:

  1. Is intended as an implant and presents a potential for serious risk to the health, safety, or welfare of a participant; or
  2. Is purported or represented to be for a use in supporting or sustaining human life and presents a potential for serious risk to the health, safety, or welfare of a participant; or
  3. Is for a use of substantial importance in diagnosing, curing, mitigating, or treating disease, or otherwise preventing impairment of human health and presents a potential for serious risk to the health, safety, or welfare of a participant; or
  4. Otherwise presents a potential for serious risk to the health, safety, or welfare of a participant.

 

Non-Significant Risk (NSR).  A non-significant risk device is an investigational device other than a significant risk device.

 

Humanitarian Use Device (HUD).  Humanitarian Use Device is a device intended to benefit patients by treating or diagnosing a disease that affects fewer than 4,000 individuals in the United States per year.

 

7.3 FDA Exemptions

The following categories of clinical investigations are exempt from the requirements of FDA regulations for IRB review:

  1. Emergency use of a test article, provided that such emergency use is reported to the IRB within 5 working days. Any subsequent use of the test article at the institution is subject to IRB review. [21CFR §56.104(c)]
  2. Taste and food quality evaluations and consumer acceptance studies, if wholesome foods without additives are consumed or if a food is consumed that contains a food ingredient at or below the level and for a use found to be safe, or agricultural, chemical, or environmental contaminant at or below the level found to be safe, by the Food and Drug Administration or approved by the Environmental Protection Agency or the Food Safety and Inspection Service of the U.S. Department of Agriculture. [21CFR §56.104(d)]

 

7.4 IND/IDE Requirements

When the principal intent of the investigational use of a test article is to develop information about the product’s safety or efficacy, an Investigational New Drug (IND) or Investigational Device Exemption (IDE) may be required.

If the protocol involves investigational drugs or devices, the investigator will be asked if there is an IND/IDE for the research and document assurances from the Sponsor that the manufacture and formulation of investigational or unlicensed test articles conform to federal regulations.  Documentation of the IND/IDE could be a:

  1. Industry sponsored protocol with IND/IDE
  2. Letter from FDA
  3. Letter from industry sponsor

 

If the research involves drugs or devices and there is no IND/IDE, the investigator will be asked for a rationale as to why it is not required. 

For drugs, an IND may not be necessary if all seven of the following conditions are met:

  1. The drug being used in the research is lawfully marketed in the United States;
  2. The research is not intended to be reported to FDA in support of a new indication for use or to support any other significant change in the labeling for the drug;
  3. The research is not intended to support a significant change in the advertising for the product;
  4. The research does not involve a route of administration or dosage level, use in a participant population, or other factor that significantly increases the risks (or decreases the acceptability of the risks) associated with the use of the drug product;
  5. The research is conducted in compliance with the requirements for IRB review and informed consent [21 CFR parts 56 and 50, respectively];
  6. The research is conducted in compliance with the requirements concerning the promotion and sale of drugs [21 CFR 312.7];
  7. The research does not intend to invoke 21 CFR 50.24 (Exception from informed consent requirements for emergency research).

 

For devices, an IDE may not be necessary if:

  1. There is a claim that it is a Non-significant risk device (NSR);
  2. The research involves a device when used or investigated in accordance with the indications in labeling in effect at that time;
  3. The research involves a device that FDA has determined to be substantially equivalent to a device in commercial distribution immediately before May 28, 1976, and that is used or investigated in accordance with the indications in the labeling FDA reviewed under subpart E of 21 CFR 807 in determining substantial equivalence;
  4. The research involves a diagnostic device, if the sponsor complies with applicable requirements in 21 CFR 809.10(c) and if the testing:
    • Is noninvasive,
    • Does not require an invasive sampling procedure that presents significant risk,
    • Does not by design or intention introduce energy into a participant, and
    • Is not used as a diagnostic procedure without confirmation of the diagnosis by another, medically established diagnostic product or procedure;
  5. The research involves a device undergoing consumer preference testing, testing of a modification, or testing of a combination of two or more devices in commercial distribution, if the testing is not for the purpose of determining safety or effectiveness and does not put participants at risk;
  6. The research involves a device intended solely for veterinary use;
  7. The research involves a device shipped solely for research on or with laboratory animals and labeled in accordance with 21 CFR 812.5(c);
  8. The research involves a custom device as defined in 21 CFR 812.3(b), unless the device is being used to determine safety or effectiveness for commercial distribution.

 

The IRB will review the application and determine:

  1. Whether there is an IND/IDE and if so, whether there is appropriate supporting documentation.
  2. If there are drugs or devices involved, but no IND/IDE, whether the research meets the above criteria.

 

7.5 Responsibilities
7.5.1.1 Investigator

  1. The investigator is responsible for ensuring that the research is conducted according to all regulatory guidelines and must obtain approval from the Brown University IRB.
  2. The investigator proposing the drug/device research will be required to provide a plan, that will be evaluated by the IRB, that will include: (a)storage, (b) security, (c) dispensing.
  3. The investigator is responsible for the investigational drug/device accountability which includes storage, security, dispensing, administration, return, disposition and records of accountability.  The investigator will delegate the responsibility for drugs/biologic accountability to the pharmacy service.
  4. If because of special circumstances, an investigational drug/device is not stored in the pharmacy, the investigator is responsible for the storage, security and dispensing of the drug/device.  The investigator must complete and submit an investigational control sheet containing information on the plan for storage, security and dispensing of the drug/device to the IRB prior to its approval of the study. All devices received for a study must be stored in a locked environment under secure control with limited access. The area must be within an area of investigator’s control. Proper instructions on the use of the drug/device must be provided to the participants. A log must be kept regarding the receipt, use and/or dispensing of the drug/device and the disposition of remaining devices at the conclusion of the investigation.
  5. The investigator shall report all unanticipated problems involving risk to participants or others to the IRB according to the procedures in this document.
  6. For research involving investigational new drugs:
    • The PI is responsible for informing the pharmacy service that IRB approval has been obtained. In addition a signed copy, of the consent form must be sent to pharmacy service to document each participant’s consent to participate in the study.
    • The PI must inform the pharmacy service when a study involving investigational drugs has been terminated.
    • The investigator shall report to the sponsor any adverse effect that may reasonably be regarded as caused by, or probably caused by, the drug according to the procedures in the protocol.
  7. For research involving investigational devices:
    • If a device considered NSR by the investigator or sponsor, is determined to have significant risk upon IRB review, the investigator is responsible for notifying the sponsor of the IRB’s determination upon receipt of written notice.  The PI should provide the IRB with confirmation of this action.
    • A copy of the protocol approval by the FDA and the IRB and the consent must be provided to the pharmacist if the device will be stored in the pharmacy. A request for the IDE and a copy of the signed consent from the research participant must be provided to the pharmacist when the device is required for use. If the investigator is storing the devices, a log must be maintained to indicate name of participant, date dispensed, by whom it was dispensed, amount remaining, and who received the device.
    • The investigator shall submit to the sponsor and to the IRB a report of any unanticipated adverse device effect occurring during an investigation as soon as possible, but in no event later than 10 working days after the investigator first learns of the effect.
  8. Following completion of the study, the termination procedure for investigational drugs must be applied if under pharmacy control.  If the devices are kept by the investigator, the log must be completed regarding the receipt, use and/or dispensing of the device, and the disposition of remaining devices at the conclusion of the investigation.
  9. When an investigator files an IND or IDE, the investigator is considered the sponsor and as such carries all of the FDA regulatory responsibilities and reporting obligations of both the Investigator and sponsor as described in the FDA regulations.  The investigator will affirm that they are aware of and will comply with the regulatory responsibilities of a sponsor.

 

7.5.1.2 IRB

 

  1. The IRB must review the research in accordance with these requirements and needs to use the same criteria it would use in considering approval of any research involving an FDA-regulated product (21 CFR 56.111).
  2. For research involving investigational devices:
    • The IRB is responsible for reviewing the protocol and determining if the device represents significant risk (SR) or non-significant risk (NSR) and report the findings to the investigator in writing. The IRB must consider the risks and benefits of the medical device compared to the risks and benefits of alternative devices or procedures. Non-significant risk device studies do not require submission of an IDE application but must be conducted in accordance with the abbreviated requirements of IDE regulations. If a study that has been submitted as NSR is considered SR, the IRB must recommend that an IDE be obtained.
    • Protocols involving significant risk devices do not qualify for expedited review.
    • The IRB must document in the Minutes the rationale for the determination of a device that is classified as NSR/SR.
    • The IRB will provide written documentation of approval to the investigator with a determination of whether the device presents a significant or non-significant risk.

 

7.6 Emergency Use
7.6.1 Emergency Exemption from Prospective IRB Approval

FDA defines emergency use as the use of an investigational drug or biological product with a human participant in a life-threatening situation in which no standard acceptable treatment is available, and in which there is no sufficient time to obtain IRB approval. If all conditions described in 21 CFR 56.102(d) exist then the emergency exemption from prospective IRB approval found at 21 CFR 56.104(c) may be utilized. Informed consent is required unless the conditions for exemption are met. The IRB must be notified within 5 working days when an emergency exemption is used. Any subsequent use of the test article at the institution is subject to IRB review.

 

If the PI notified the IRB prior to the emergency use of an investigational test article, the circumstances will be reviewed by IRB staff to determine that it meets FDA regulations and the investigator will be advised accordingly.   All after-the-fact reports to the IRB of emergency use will be reviewed by IRB staff to determine the circumstances and for compliance with FDA regulations.

 

7.6.2 Emergency Waiver of Informed Consent

An exception under FDA regulations at 21 CFR 50.23 permits the emergency use of an investigational drug, device, or biologic without informed consent where the investigator and an independent physician who is not otherwise participating in the clinical investigation certify in writing all four of the following specific conditions: 

  1. The participant is confronted by a life-threatening situation necessitating the use of the test article;
  2. Informed consent cannot be obtained because of an inability to communicate with, or obtain legally effective consent from, the participant;
  3. Time is not sufficient to obtain consent form the participant’s legally authorized representative;
  4. No alternative method of approved or generally recognized therapy is available that provides an equal or greater likelihood of saving the participant’s life.

 

If time is not sufficient to obtain the independent physician determination before use of the test article, the actions of the investigator must be reviewed and evaluated in writing by an independent physician within 5-6 working days.  The emergency use must be reported to the IRB within 5 working days.  This reporting must not be construed as an approval for the emergency use by the IRB.

 

7.6.3 Treatment IND

FDA regulations (21 CFR 312.34 and 312.35) address the treatment use of an investigational drug (not approved for marketing, but under clinical investigation for a serious or immediately life-threatening disease condition) in patients for whom no comparable or satisfactory alternative drug or other therapy is available. Use of the investigational drug for this purpose must meet all applicable FDA requirements.

 

7.6.4 Emergency Waiver of IND

FDA regulations at 21 CFR 312.34, 312.35, and 312.36 address the need for an investigational drug to be used in an emergency situation that does not allow time for submission of an IND. The FDA may authorize shipment of the drug for a specific use in such a circumstance in advance of submission of an IND. Prospective IRB review is required unless the conditions for exemption are met (21 CFR 56.104(c) and 56.102(d)). Informed consent is required unless the conditions for exemption are met (21 CFR 50.23). All applicable regulations must be met including those at 21 CFR Parts 50 and 56, and 21 CFR 312.34 and 312.35.

 

7.7 Waiver of Informed Consent for Planned Emergency Research

The conduct of planned research in life-threatening emergencies where the requirement to obtain prospective informed consent has been waived is covered by 21 CFR §50.24. The research plan must be approved in advance by the FDA or DHHS and the IRB, and publicly disclosed to the community in which the research will be conducted. Such studies are not allowed under the regulations covering the emergency use of a test article in a life-threatening situation (21 CFR §56.104(c).

 

7.8 Humanitarian Use Devices (HUD)

In accordance with 21 CFR 814.124, treatment with a HUD is subject to full board initial and continuing review by the IRB.  At the time of review, the IRB will determine if written consent from participants for use of the HUD is necessary. If a physician in an emergency situation determines that IRB approval cannot be obtained in time to prevent serious harm or death to a patient, a HUD may be administered without prior IRB approval.  In this instance, approval must be obtained from the appropriate local authority (such as the Chief of Staff), and the investigator is required to provide written notification of the use to the IRB within five days after use of the device. The IRB requires that written notification include identification (specification without identifiers) of the patient, the date on which the device was used, and the reason for the use.  It is the responsibility of the investigator to notify the FDA if the IRB were ever to withdraw approval for use of a HUD.  The FDA should be notified within five days of notification of the withdrawal of approval. Investigators are reminded that Humanitarian Device Exemptions are for clinical use only and HUDs can be used only for purposes outlined in the approved IRB application.

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