Revolution by Phases: FDA's Regulation of Investigational Device Exemptions

Medical Device & Diagnostic Industry Magazine
MDDI Article Index

Jonathan S. Kahan

The collection and evaluation of clinical data to demonstrate the safety and efficacy of a medical device are absolutely essential for the ultimate premarket approval of all Class III devices. Under premarket approval (PMA) regulations, FDA requires the submission and review of valid scientific evidence to determine whether a reasonable assurance exists that the device is safe and effective, and has clinical utility.

As defined in the regulations, valid scientific evidence consists of data from well-controlled investigations, partially controlled studies, studies and objective trials without matched controls, well-documented case histories compiled by qualified experts, and reports of significant human experience with a marketed device.¹ Notwithstanding the language of the regulations, FDA has interpreted the valid scientific evidence requirement as essentially limited to well-controlled investigations--which, as will be discussed, has led it to institute stringent requirements for the randomization and blinding of clinical trials.

Although clinical trial issues have historically been linked primarily to PMA submissions, they are also becoming more crucial to the marketing clearance of devices proceeding through the 510(k) premarket notification process. While it is difficult to obtain reliable information as to the number of 510(k) notices that are actually supported by well-controlled clinical data, FDA policies under Commissioner David Kessler have clearly led to requirements for greater data support for 510(k) notices, including increased requests for performance testing of Class II devices. Such performance testing can range from mechanical and other bench testing to animal and human clinical studies. It appears that the number of 510(k) premarket notifications supported by clinical trial data has jumped from 2­4% prior to 1990 to approximately 10% in 1995. This increase has led to a much more heightened awareness of clinical trial issues in the medical device industry.

The motivation for FDA's increased emphasis on clinical data can be traced directly to Commissioner Kessler's concern that the Office of Device Evaluation (ODE) in the Center for Devices and Radiological Health (CDRH) was not adequately evaluating the underlying clinical support for many device clearances. Kessler was especially concerned about the lack of clinical information and analysis relating to the ODE clearance of 510(k) notices for preamendment Class III silicone-gel breast implants. Consequently, he requested that Robert Temple, director of the Office of Drug Evaluation I at the Center for Drug Evaluation and Research (CDER), form a committee of CDER physicians and biostatisticians to evaluate the ODE clinical review process.

Under Temple's direction, the Committee for Clinical Review looked at numerous PMA applications, investigational device exemption (IDE) applications, and 510(k) premarket notifications to determine whether the underlying studies had been properly designed and conducted, and whether ODE had appropriately evaluated the trial data. In March 1993, the Temple Report was released.² The committee found the following design deficiencies in the clinical data submissions received and evaluated by ODE:

From March 1993 forward, the criticisms leveled by the Temple committee have been the driving force for most IDE clinical design decision making. As will be discussed later in this article, the entire IDE application process underwent a sea change in the period from 1990 through 1995. Indeed, some who have been involved in the process believe that ODE's thinking as to what is an appropriate design for the study of medical devices has undergone a revolution, not just evolution. With this background, it is possible to understand more fully the IDE process about to be described.

Clinical studies that are designed to evaluate the safety and effectiveness of a medical device are covered by the IDE regulations at 21 CFR 812. A sponsor of a clinical study must submit an IDE application to ODE for all studies that are intended to include a significant- risk (SR) device, such as an implantable pacemaker or an implantable orthopedic prosthesis. For non-significant-risk (NSR) devices, the sponsor is still required to follow the IDE regulations at 21 CFR 812, but no IDE application need be approved by FDA prior to the initiation of the clinical trial. Nevertheless, under the abbreviated IDE requirements for NSR devices, institutional review board (IRB) approval must still be obtained prior to initiation of the study, and requirements covering appropriate informed consent, recordkeeping, and adverse-effect reporting are still applicable.

Significant-Risk versus Non-Significant-Risk Device Studies. In initiating a clinical trial, one of the first steps that a study sponsor must take is to decide whether the device is SR or NSR. A significant- risk device is defined as one that:

1. Is intended as an implant and presents a potential for serious risk to the health, safety, or welfare of a research subject.

2. Is purported or represented to be for use in supporting or sustaining human life and presents a potential for serious risk to the health, safety, or welfare of a research 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, or welfare of a research subject.

4. Otherwise presents potential for serious risk to the health, safety, or welfare of a research subject.³

In order to assist sponsors in determining whether their device is SR or NSR, FDA issued a guidance document in June 1986 entitled "Guidance on Significant and Nonsignificant Risk Device Studies." This guidance document, which was updated in 1994, provides a list of examples of NSR and SR devices.⁴ In most instances, a sponsor will be able to make a fairly straightforward decision as to whether the device requires an IDE application because it is an SR device. However, even if a device is an NSR product, it is still best to review the study protocol with ODE even though no IDE application has been filed.

The rationale for discussing NSR device investigational plans with ODE prior to study initiation is that the office may have questions with respect to the design of the study, the success criteria and end points, the inclusion or exclusion criteria for the study, the sample size, or the case report forms. It is much better to have ODE input before beginning the study than to have FDA inform the sponsor at its conclusion that the study design was inappropriate and that, therefore, in order to obtain 510(k) clearance or premarket approval, the company must repeat the study under a new protocol.

Exempt Studies. In some cases, unapproved and uncleared devices are exempt from the IDE requirements. The most prominent of these exempt devices are the following:

Finally, there are several other exemption categories that merit only passing reference. Studies involving certain preamendment devices, devices found to be substantially equivalent, and veterinary devices are also exempt from the IDE requirements.