Investigational Device Exemption (IDE)

IDE Investigator Responsibilities

Investigational device exemptions (IDEs) are approved in two different ways depending on whether the study involves a significant risk device or not. Investigations of significant risk devices require the sponsor to submit a separate application for an IDE approval along with its application for pre-market approval to the FDA. Investigations of non-significant risk devices have abbreviated requirements for an IDE [21 CFR 812.2(b)].

One of these requirements calls for the sponsor, generally through the investigator, to present information explaining why the device should be categorized as a non-significant risk device as part of the IRB review. When all of the abbreviated requirements are met (i.e., IRB approval, informed consent, record-keeping, labeling, promotion, and study monitoring), the investigation is considered to have an approved IDE without need for filing a separate IDE application to FDA.

By definition, a significant risk device is an investigational device that:

1. Is intended as an implant and presents a potential for serious risks to the health, safety, and welfare of a subject;
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, and welfare of a subject;
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, and welfare of a subject; or
4. Otherwise presents a potential for serious risk to the health, safety, and welfare of a subject (21 CFR §812.3(m)).

The responsibilities for investigators conducting investigations on devices are analogous to those for investigators conducting studies on drugs. See 21 CFR parts 11, 54, 812, 814, 820; FDA Center for Devices and Radiological Health; UAB HRPP "PRO141 Procedure to Ensure Handling of Investigational or Unlicensed Test Articles Meets Organizational Standards Relating to Devices, Inventory Control and Documentation."

Generally, the investigator is responsible for ensuring that an investigation is conducted according to the signed written agreement, the investigational plan and applicable FDA regulations; for protecting the rights, safety, and welfare of subjects under the investigator´s care; and for control of the devices under investigation.

Also, an investigator is responsible for obtaining informed consent in accordance with regulations (21 CFR §812.100). These general requirements translate into the following specific responsibilities:

• An investigator must not request the written informed consent of any subject to participate, and must not allow any subject to participate before obtaining IRB and FDA approval. (However, an investigator may determine whether potential subjects would be interested in participating in an investigation.)
• An investigator must conduct the investigation in accordance with the signed agreement with the sponsor, the investigational plan, any applicable FDA regulations, particularly those on investigational devices, and any conditions of approval imposed by an IRB or FDA.
• An investigator must permit an investigational device to be used only with subjects under the investigator’s supervision. An investigator must not supply an investigational device to any person unauthorized under the regulations to receive it.
• A clinical investigator must disclose to the sponsor sufficient, accurate financial information to allow the applicant to submit complete and accurate financial disclosure statements under the regulations.
• Upon completion or termination of a clinical investigation or the investigator’s part of the investigation, or at the sponsor’s request, an investigator shall return to the sponsor any remaining supply of the device or dispose of the device in accordance with the sponsor’s directions (21 CFR §812.110).

In addition, the regulations require participating investigators to discharge obligations with regard to records, inspections, and reports.

Records (21 CFR 812.140)

Investigators records. Participating investigators must maintain the following accurate, complete, and current records relating to the investigator’s participation in an investigation:

1. All correspondence with another investigator, an IRB, the sponsor, a monitor, or FDA, including required reports.
2. Records of receipt, use, or disposition of a device that relates to:
   1. The type and quantity of the device, the dates of its receipt, and the batch number or code mark.
   2. The names of all persons who received, used, or disposed of each device.
   3. Why and how many units of the device have been returned to the sponsor, repaired, or otherwise disposed of.
3. Records of each subject’s case history and exposure to the device. These records must contain:
   1. Documentation of informed consent and, for any use of a device without informed consent, the written concurrence of a licensed physician and brief description of the circumstances justifying the failure to obtain informed consent.
   2. All relevant observations, including records of anticipated and unanticipated adverse device effects; information and data on the condition of each subject upon entering, and during the course of, the investigation, including information about relevant past medical history and results of all diagnostic tests.
   3. A record of exposure of each subject to the investigational device, including the date and time of each use, and any other therapy.
4. The protocol, with documents showing the dates of and reasons for each deviation from the protocol.
5. Any other records that FDA requires to be maintained by regulation or specific requirement for a category of investigations or a particular investigation.
6. An investigator or sponsor must retain the records and reports required under the device regulations during the investigation and for 2 years after the latter of the following two dates: The date on which the investigation is terminated or completed, or the date that the records are no longer required for purposes of supporting a premarket approval or a notice of completion of a product development protocol.
7. An investigator or sponsor may withdraw from the responsibility to maintain records for the periods stated in (6) above and transfer custody to any other person who will accept responsibility for them under the investigational device regulations including the inspection requirements. Notice of transfer must be given to FDA not less than 10 days after transfer occurs.

Inspections (21 CFR §812.145)

Authorized FDA personnel have jurisdiction to inspect facilities and records as listed below:

• Entry and inspection of facilities. An investigator with authority to grant access must permit authorized FDA employees, at reasonable times and in a reasonable manner, to enter and inspect any facility where devices are installed, used, or implanted or where records of results from use of devices are kept.
• Records inspection. An investigator, or any other person acting on the investigator’s behalf with respect to an investigation, must permit authorized FDA employees, at reasonable times and in a reasonable manner, to inspect and copy all records relating to an investigation.
• Records with subjects’ identity information. An investigator must permit authorized FDA employees to inspect and copy records that identify subjects, after receiving notice that FDA has reason to suspect that adequate informed consent was not obtained, or that reports required to be submitted by the investigator to the IRB or sponsor have not been submitted or are incomplete, inaccurate, false, or misleading.

Reporting (21 CFR §812.150)

An investigator must prepare and submit the following reports in a timely, accurate, and complete manner:

• Unanticipated adverse device effects. An investigator must submit to the sponsor and to the reviewing 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 learns of the effect.
• Withdrawal of IRB approval. An investigator must report to the sponsor, within 5 working days, a withdrawal of an approval by the reviewing IRB of the investigator’s part of an investigation.
• Progress. An investigator must submit progress reports on the investigation to the sponsor, the monitor, and the reviewing IRB at regular intervals, but in no event less than annually.
• Deviations from the investigational plan. An investigator must notify the sponsor and the reviewing IRB of any deviations from the investigational plan to protect the life or physical well-being of a subject in an emergency. This notice must be given as soon as possible but in no event later than 5 working days after the emergency occurred. Except in such emergency, prior approval by the sponsor is required for changes in a deviation from a plan, and if these changes or deviations may affect the scientific soundness of the plan or the rights, safety, or welfare of human subjects, approval from FDA and the IRB in accordance with FDA regulations.
• Informed consent process. If an investigator uses a device without obtaining informed consent, the investigator must report such use to the sponsor and the reviewing IRB within 5 working days after initiating the use.
• Final report. An investigator must, within 3 months after termination or completion of the investigation or the investigator’s part of the investigation, submit a final report to the sponsor and reviewing IRB.
• Other. An investigator shall, upon request by a reviewing IRB or FDA, provide accurate, complete, and current information about any aspect of the investigation.

IDE Sponsor Requirements

If you are the sponsor and the investigator for the device, you must meet the requirements for the sponsor and the investigator.

This is an overview of the FDA sponsor requirements contained in 21 CFR 812 for research with investigational devices. This overview is intended to assist the sponsors in identifying and complying with their responsibilities in connection with the conduct of clinical investigations of medical devices that are deemed "significant risk" by the reviewing IRB or by the FDA.

Other FDA regulations for sponsors include, but are not limited to, 21 CFR Parts 11, 54, 814, and 820. Please review the federal regulations before performing any sponsor duties. In addition, sponsors should be aware that a clinical investigation must be conducted in accordance with any requirements imposed by the reviewing IRB, by institutional policies, or by state law.

Additional information can be found on the FDA´s web site: http://www.fda.gov/cdrh/mdr

General Duties (21 CFR 812.40)

• Selects qualified investigators;
• Provides investigators with information they need to properly conduct the investigation;
• Ensures proper monitoring;
• Ensures IRB review and approval are obtained;
• Submits the IDE application to the FDA;
• Ensures that any reviewing IRB and FDA are promptly informed of significant new information about an investigation;
• Does not begin an investigation or part of an investigation until an IRB and the FDA have both approved the application or supplemental application relating to the investigation or part of the investigation.

Selection of Investigators (21 CFR 812.43)

• Selects investigators qualified by training and experience to investigate the device;
• Ships the investigational device only to participating qualified investigators;
• Obtains a signed investigator's agreement from each participating investigator that includes:
  • investigator's curriculum vitae
  • statement of investigator's relevant experience, including dates, location, extent, and type of experience, where applicable;
  • if an investigator was involved in an investigation or other research that was terminated, an explanation of the circumstances that led to the termination
  • statement of the investigator's commitment to:
    • conduct the investigation in accordance with the agreement, the investigational plan, 21 CFR 21 Parts 50, 56, and 812, and any conditions of approval imposed by the IRB or FDA
    • supervise all testing of the device involving human subjects
    • ensure that the requirements for informed consent are met (21 CFR Part 50
• Supplies investigators participating in the investigation with copies of the:
  • investigational plan
  • report of prior investigations.

Monitoring (21 CFR 812.46)

• Selects monitor(s) qualified by training and experience to monitor the progress of the investigation;
• Secures prompt compliance or discontinues shipments of the device to the investigator and terminates the investigator’s participation in the investigation, upon discovery that an investigator is not complying with the signed agreement, the investigational plan, the requirements of applicable FDA regulations, or any conditions of approval imposed by the reviewing IRB or the FDA;
• Requires any investigator terminated from participation in an investigation to dispose or return the device, unless this action would jeopardize the rights, safety, or welfare of the subject;
  • Conducts immediately an evaluation of any unanticipated adverse device effect and terminates all investigations or parts of investigations whenever the sponsor determines that an unanticipated device effect presents an unreasonable risk to subjects. Termination shall occur:
  • Not later than 5 working days after the sponsor makes this determination; and
  • Not later than 15 working days after the sponsor first received notice of the effect.
• Resumes terminated investigations as follows:
  • If the device is a significant risk device, only after both FDA and IRB approvals are obtained;
  • If the device is a non-significant risk device, only after IRB approval and FDA approval if the termination was due to an unanticipated adverse device effect.

Controlling Distribution and Disposition of Devices

Although investigators are responsible for ensuring that investigational devices are made available only to persons who are legally authorized to receive them (see 21 CFR §812.110(c)), sponsors also bear responsibility for taking proper measures to ensure that devices are not diverted outside of legally authorized channels. Sponsors may ship investigational devices only to qualified investigators participating in the clinical investigation (§812.43(b)).

Sponsors must also maintain complete, current, and accurate records pertaining to the shipment and disposition of the investigational device (§812.140(b)). Records of shipment shall include the name and address of the consignee, type, and quantity of device, date of shipment, and batch number or code mark. Records of disposition shall describe the batch number or code marks of any devices returned to the sponsor, repaired, or disposed of in other ways by the investigator or another person, and the reasons for and method of disposal.

To ensure further compliance with these requirements, sponsors should take appropriate measures to instruct investigators regarding their responsibilities with respect to recordkeeping and device disposition. The specific recordkeeping requirements for investigators are set forth at §812.140(a).

Upon completion or termination of a clinical investigation (or the investigator's part of an investigation), or at the sponsor's request, an investigator is required to return to the sponsor any remaining supply of the device or otherwise to dispose of the device as the sponsor directs (§ 812.110(c)).

Prohibition of Promotion and Other Practices (21 CFR 812.7)

The IDE regulations prohibit the promotion and commercialization of a device that has not been cleared or approved for marketing by FDA. This prohibition is applicable to sponsors and investigators (or any person acting on behalf of a sponsor or investigator), and encompasses the following activities: · Promotion or test marketing of the investigational device; · Charging subjects or investigators for the device a price larger than is necessary to recover the costs of manufacture, research, development, and handling; · Prolonging an investigation beyond the point needed to collect data required to determine whether the device is safe and effective; and, · Representing that the device is safe or effective for the purposes for which it is being investigated.

Supplemental Applications [21 CFR 812.35(a) and (b)]

Supplemental applications are required to be submitted to, and approved by the FDA in the following situations:

• Changes in the investigational plan: FDA approval is required for any change that may affect the scientific soundness of the investigation or the rights, safety or welfare of the subjects. IRB approval is also required for changes that may affect the rights, safety, or welfare of the subjects. The change in the investigational plan may not be implemented until FDA approval (and IRB approval, if required) is obtained.
• Addition of new institutions: IRB approval is also required for new institutions. The investigation at the new institution(s) may not begin until both FDA and IRB approval(s) are obtained, and certification of IRB approval is submitted to FDA.

Maintaining Records [21 CFR 812.140(b)]

A sponsor shall maintain the following accurate, complete, and current records relating to an investigation: · All correspondence (including reports) with another sponsor, monitor, investigator, IRB or the FDA; · Records of shipment must include: ? name and address of consignee; ? type and quantity of device; ? date of shipment; ? batch numbers or code marks. · Records of disposition must describe: ? batch number or code mark of any devices; § returned to the sponsor; § repaired, or § disposed of by the investigator or another persons; and § reasons for and method of disposal. · Signed investigator agreements, including the financial disclosure information required by 21 CFR Part 54; · Adverse device effects (whether anticipated or unanticipated) and complaints; · Any other records that the FDA requires by regulation or by specific requirement for a category of investigation or a particular investigation; · For each investigation of a device other than a significant risk device subject to abbreviated requirements of 21 CFR 812.20(b)(1), maintains the following records consolidated in one location and available from FDA inspection and copying:

Summary of IDE Record-Keeping Requirements

The Summary of IDE Record-Keeping Requirements table, below, shows the responsibilities for record maintenance by Investigator and Sponsor.

Inspections [21 CFR 812.145]

Sponsors are required to permit FDA to enter and inspect (at reasonable times and in a reasonable manner) any establishment where devices are held (including any establishment where devices are manufactured, processed, packed, installed, used, or implanted or where records or results from use of devices are kept). The FDA may also inspect and copy all records relating to an investigation including, in certain situations, records which identify subjects.

There are other sponsor responsibilities beyond the scope of this summary (e.g., quality system regulation (21 CFR 820)). If you have questions, contact UAB Office of Counsel.

Humanitarian Use Device (HUD) Faculty Responsibilities

Occasionally, faculty wish to engage in clinical activities involving a HUD. In general separate regulations from the IDE regulations apply to HUDs. These regulations allow pre-marketing approval of an HUD through a special application procedure termed a humanitarian device exemption (HDE).

HDE regulations require HUDs to be used only in facilities that have an IRB constituted in accordance with FDA regulations and the proposed uses of the device to undergo initial and continuing review by that IRB or by another IRB to which the facility´s IRB deferred.

In the case of HUDs, IRBs are being asked to review non-research activity under the FDA regulations for clinical investigation. Informed consent process requirements under the HUD regulations do not apply, but the IRB may impose this as an additional request. Because the HUD regulations are not research regulations per se, no investigator responsibilities are explicitly listed.

There are numerous responsibilities, such as reporting requirements, placed on the holder of the HDE; however, many of these requirements will have to be met through the HUD users actions. To further complicate matters, HUDs may be involved in clinical investigations, in which case IRB approval of the clinical investigation under human protections regulations must be obtained.

UAB faculty members using HUDs should be aware of the following obligations under the HUD regulations:

• Use of the HUD must undergo initial and continuing review and approval.
• Any emergency use of a HUD to prevent serious harm or death to a patient without prior local IRB approval must be reported by the physician to the IRB within 5 days after the use of the device.
• Any withdrawal of approval for use of a HUD by an IRB must be reported promptly to the holder of the HDE.
• All correspondence with the IRB must be submitted to the approved HDE holder.
• All medical device reports (MDRs) submitted to FDA by the approved HDE holder must also be submitted to the IRB.
• Any MDRs listing reportable events sent to the user of the HUD must be forwarded to the IRB.