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:
- Failure to specify a clear hypothesis to be tested and to develop a clear plan to test it.
- Failure to enroll a sufficient number of patients to answer the primary study questions.
- Failure to adequately specify requirements for patients entering studies.
- Failure to identify a control group.
- Failure to assess properly the comparability of patients in the treatment and control groups.
- Failure to clearly and precisely define end points.
- Failure to implement blinded evaluation of end points, especially when they were subjective in nature.
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:
- Diagnostic Devices. A diagnostic device is exempt from the requirements of 21 CFR 812 if the testing is noninvasive, does not require an invasive sampling procedure that presents significant risk, does not by design or intent introduce energy into a subject, and is not used as a diagnostic procedure without confirmation of the diagnosis by another medically established product or procedure.5 In vitro diagnostics (IVD) that are exempt from the IDE requirements under 21 CFR 812 must still meet the requirements for appropriate labeling of "investigational or research use only diagnostics."6 A research-use-only device must be labeled "For Research Use Only. Not for use in diagnostic procedures."7 Similarly, investigational-use-only IVDs must be labeled "For Investigational Use Only. The performance characteristics of this product have not been established."
- Consumer Preference Testing. A device is also exempt from the IDE requirements if it is 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 subjects at risk. FDA takes a very narrow view as to whether a device is actually exempt from the IDE requirements because it is undergoing consumer preference testing. Indeed, if there is even a hint that the study is being conducted to determine the safety or effectiveness of the device, then the IDE requirements must be met.
- Laboratory Testing. Devices shipped solely for research on or with laboratory animals and labeled "CAUTION--Device for investigational use in laboratory animals or other tests that do not involve human subjects" are exempt from the IDE requirements.
- Custom Devices. Custom devices are also exempt from the IDE requirements. A custom device is defined as one that: (1) necessarily deviates from devices generally available or from an applicable performance standard or premarket approval requirement in order to comply with the order of an individual physician or dentist; (2) is not generally available to, or generally used by, other physicians or dentists; (3) is not generally available in finished form for purchase or for dispensing upon prescription; (4) is not offered for commercial distribution through labeling or advertising; and (5) is intended for use by an individual patient named in the order of a physician or dentist and is to be made in a specific form for that patient, or is intended to meet the special needs of the physician or dentist in the course of professional practice.8 Again, FDA takes a very narrow view as to whether shipment of an unapproved, uncleared device is in fact the distribution of a custom device not subject to the IDE requirements. The agency is presently developing a guidance document for industry relating to the appropriate definition of custom device. Suffice it to say at this time, however, that the shipment of any significant number of unapproved or uncleared devices under the custom device rationale may not be able to withstand FDA scrutiny.
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.