Devices

In accordance with the Federal Food, Drug, and Cosmetic Act, FDA places all medical devices into one of three regulatory classes based on the level of control necessary to ensure safety and effectiveness of the device. Classification is risk based, that is, the risk the device poses to the patient and/or the user is a major factor in determining the class to which it is assigned.

Devices in all three classes are subject to general controls which require, in part, that companies: (1) register their establishments and list the medical devices they market with FDA; (2) manufacture their devices in accordance with Good Manufacturing Practices; and (3) label their devices in accordance with labeling regulations.

Class I devices are subject only to general controls. They typically present the lowest potential for harm and are simpler in design than Class II or Class III devices. Examples of Class I devices include elastic bandages, examination gloves, and hand-held surgical instruments.

Class II devices are those for which general controls alone are insufficient to provide a reasonable assurance of safety and effectiveness. In addition to complying with general controls, Class II devices are also subject to special controls identified by the agency, which may include special labeling requirements, performance standards and postmarket surveillance. Examples of Class II devices include powered wheelchairs, infusion pumps, and surgical drapes.

Class III devices generally are those for which insufficient information exists to determine that general or special controls are sufficient to provide a reasonable assurance of safety and effectiveness. Examples of Class III devices include replacement heart valves, silicone gel-filled breast implants, and implanted cerebellar stimulators. The premarket approval process (PMA)is the FDA process of scientific and regulatory review to evaluate the safety and effectiveness of class III medical devices.

Excerpted from Information Sheet Guidance For IRBs, Clinical Investigators, and Sponsors. Frequently Asked Questions About Medical Devices, 2006

FDA Regulatory Approval Pathways

The regulatory pathway for approval by the FDA depends on whether or not there is an existing device that is substantially equivalent – a predicate device – and the number of potential patients who might use the device. Whether or not clinical trials are required to support the approval of a new device will depend on these factors.

Premarket Approval is the regulatory pathway for devices for devices that do not have a predicate device or where the new device is not substantially equivalent. These devices require reasonable evidence of safety and effectiveness to obtain FDA approval. Once a device has received FDA PMA, supplements are often submitted to modify the device. Supplements are reviewed via 5 different pathways, the majority of which do not to require any clinical trials. Manufacturers tend to release multiple minor changes rather than releasing a single substantive change allowing them to avoid the need to conduct additional clinical trials. For a more in depth discussion see Rome et al. FDA Approval of Cardiac Implantable Electronic Devices via Original and Supplement Premarket Approval Pathways, 1979-2012.

Premarket Notification - 510(k) is the regulatory pathway for devices that are substantially equivalent to a predicate device. Clinical trials and data in humans are not required for devices approved via this pathway. Requiring clinical trials for every minor change to medical devices would be expensive. Minor changes to devices as complex as heart valves, joint replacements, surgical instruments, implanted pacemakers, or insulin pumps might not require any clinical trials if there is a predicate device that can be referenced. Sometimes the ancestry of a predicate device can be quite labyrinthine and involve dozens of devices. The 510(k) Ancestry of a Metal-on-Metal Hip Implant outlines the long a twisted history of the various predicate devices that allowed metal-to-metal hip implants approval under the 510(k) pathway. For a history of the successes and failures of the 510(k) approval process see the Institute of Medicine Report Medical Devices and the Public Health. The FDA 510(k) Clearance Process at 35 Years.

Humanitarian Device Exemption is the regulatory pathway for devices for devices that are intended for certain rare conditions where it would not be possible to develop sufficient evidence of safety and effectiveness to support a PMA.

Humanitarian Device Exemption is the regulatory pathway for devices for devices that are intended for certain rare conditions where it would not be possible to develop sufficient evidence of safety and effectiveness to support a PMA.

A Humanitarian Device Exemption (HDE) application is similar to a premarket approval (PMA) application. However, due to the limited size of the target population and the impracticability of conducting clincal trials to establish safety and effectiveness, an HDE is exempt from the requirement to establish reasonable assurance of effectiveness. The FDA's approval is based on its determination that the device will not expose patients to an unreasonable risk of injury or illness and the "probable benefit" to health. This is a considerably lower standard than proof of safety and effectiveness.

FDA approval of an HDE authorizes an applicant to market the HUD, subject to certain profit and use restrictions. HUDs cannot be sold for profit, except in very limited circumstances. Most importantly, they can only be used in a facility after an IRB has approved their use in that facility, except in certain emergencies.

How is an HDE different from an IDE?

An IDE is an exemption that allows a sponsor to ship an investigational device prior to marketing approval; it authorizes the investigational use of the device. A HUD with an approved HDE is approved for marketing. This means that the sponsor can ship the device and can bill for its use (but cannot make a profit from its sale except under limited circumstances). To receive approval for an HDE, the FDA must conclude that there is no comparable device available to treat the disease or condition. If a comparable device is approved by the FDA, the HDE approval may be withdrawn. An HDE therefore is analogous to a PMA application; its an application to market the device. An IDE is an application to ship an investigational device to conduct studies.

To approve a PMA device, the sponsor has to provide data from adequate and well-controlled trials that provide substantial evidence of effectiveness (and safety). The requirements for approval of an HDE application to market a HUD are quite a bit lower. FDA's Q&A states that an approved HDE represents "a determination by FDA that the HUD will not expose patients to an unreasonable or significant risk of illness or injury and the probable benefit to health from use of the device outweighs the risk of injury or illness from its use while taking into account the probable risks and benefits of currently available devices or alternative forms of treatment."

What are the IRB's Responsibilities for a HUD?

A. Clinical use of a HUD for treatment or diagnosis in accordance with the approved label or off-label

1. Clinical use of a HUD for treatment or diagnosis in accordance with the approved label or off-label

   After HDE approval, a HUD may only be used after IRB approval has been obtained for the use of the device, even for the FDA-approved indication, except for an emergency use situation. The IRB is required to perform its initial review at a convened meeting using the criteria for approval at 21 CFR 56.111. Subsequent continuing reviews - at least annually - may be performed using expedited procedures. Expedited review is permitted because a HUD is an approved device.

2. Emergency use of a HUD for clinical care in a single patient

   The healthcare provider is required to comply with the requirements of the Emergency Use of Investigational Drugs, Biologics, or Devices SOP (IRB SOP 802, V.C.1-3, and 5). The IRB will review the 5-day report in accordance with IRB SOP 802.

B. Investigational use of a HUD in accordance with the approved label or off-label

1. Investigational use in accordance with the approved label to collect safety and effectiveness data

   The IRB will review the initial study at the convened board.

2. Investigational use off label

   The IRB will review the study at the convened board. The proposed use will need to be in compliance with FDA regulations under 21 CFR 50, 56, and 812 (e.g. may require submission of an IDE application to FDA or be conducted under the abbreviated requirements for NSR devices at 21 CFR 812.2(b)).

For details on the requirements for initial submission to the IRB, continuing reviews, amendments, and adverse event reporting, see the Humanitarian Use Device (HUD) SOP (IRB SOP 412).

References

• 21 CFR 814. See Subpart H - Humanitarian Use Devices, which contain the regulations governing HUDs.
• FDA Guidance Document Humanitarian Use Device (HUD) Designations issued September 5, 2019.
• FDA Guidance Document Humanitarian Device Exemption (HDE) Program issued September 6, 2019.
• Institutional Review Boards and Humanitarian Use Device (HUD) Powerpoint learning module presented by Dr. Fabienne Santel of the Center for Devices and Radiological Health at the FDA.