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<B>Continuation of MDDI's January 1996 article, "Revolution by Phases: FDA's regulation of Investigational Device Exemptions"</B>

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Although it is probably belaboring the obvious, the design and conduct of the clinical trial are the keys to ultimate marketing approval of the device. The data generated by the clinical trial must support the claims that the sponsor intends to make for the marketed device and the clinical utility of the device. In other words, if the sponsor wishes to market the device for use in a specific study population, that population must be included in the clinical trial. Similarly, if the ultimate instructions for use of the product will recommend a specific power setting or duration of use, these must be evaluated in the clinical trial. If prior to initiating the clinical trial the company is unsure as to what settings or duration of use are appropriate, then a feasibility study may be called for. ODE has been encouraging companies to conduct "pilot" or "feasibility" studies prior to the initiation of clinical trials to resolve such issues as device design and operating specifications and to better define patient populations and device indications.

ODE has issued a guidance document regarding feasibility studies which is entitled "Guidance on the Review of Investigational Device Exemptions (IDE) Applications for Feasibility Studies."12 Under that guidance, an IDE application for a feasibility study must address all of the elements of a standard IDE application. However, the study is typically conducted with a smaller number of patients, often 10 or fewer and rarely more than 20. Feasibility studies are often conducted at only one or two institutions with very specific end points in mind. For example, if a software algorithm is necessary for the appropriate operation of the device, the company may wish to evaluate and finalize that algorithm in a limited study rather than proceed to a trial with an algorithm that is uncertain with respect to ultimate safety or efficacy. Once a feasibility study is completed, the company can often then submit an IDE supplement to expand the study to the pivotal clinical trial.

After the company has made the decision to proceed to the pivotal clinical trial, trial design becomes of foremost importance. In September 1993, FDA issued a guidance document entitled "Medical Device Clinical Study Guidance," in which it covers in great detail the issues that should be considered in the design of a clinical trial.13 It should be mentioned that many of the recommendations in this guidance document can be traced directly to concerns enunciated in the Temple Report.

Without going into the clinical study guidance document in great detail, it contains several points worth mentioning. First, it appropriately states that good clinical study design controls minimize known or suspected sources of bias and other errors so that clinical device performance can be assessed clearly. One of the primary concerns of ODE since release of the Temple Report has been the need to reduce potential study biases that result when any characteristic of the investigator, study population, or study conduct interferes in any way with the ability to measure a variable accurately.

Second, the guidance document emphasizes that the study population and the control population must be well-defined. It discusses active concurrent controls, passive concurrent controls, self controls, and historical controls. It mentions, however, that active concurrent controls and, where applicable, self controls allow the greatest degree of opportunity for comparability.

Experience over the past several years has revealed that active concurrent controls with appropriate randomization and blinding are the key elements FDA considers for appropriate clinical design. While almost all PMA applications prior to 1990 were approved based upon comparison of the study results to historical controls, FDA now accepts historically controlled studies only in the rarest of instances. Partly because of the influx of CDER personnel into CDRH, the drug model for clinical trials--which is grounded upon randomized, double-blinded, and controlled trials--has become the gold standard for medical device studies as well. The September 1993 guidance document makes it very clear that "historical controls are the most difficult to assure comparability with the study population" and "will usually require much more work to validate comparability than concurrent controls." Therefore, unless absolutely necessary for ethical or other reasons, historical controls should be relied upon sparingly in proving the safety and efficacy of a new device.

Studies for IVDs also raise quite different issues from studies for other medical devices. First, very few IVD clinical trials are conducted under the IDE regulations. Because they involve exempt diagnostics, they typically proceed without the filing of an IDE application. Nevertheless, because of the importance of the clinical study data to the ultimate clearance or approval of the device, most IVD manufacturers review their study protocols with the ODE Division of Clinical Laboratory Devices (DCLD) prior to initiation of their clinical trials.

DCLD has many guidances that apply to specific diagnostics, and they should be reviewed very carefully by IVD study sponsors. For example, the guidance document "Review Criteria for Premarket Approval of In-Vitro Diagnostic Devices for Detection of Antibodies to Parvovirus B19" contains a very detailed section on clinical studies.14 It discusses how clinical confirmation of infection may be conducted, how the test sample should be submitted to the clinical laboratory, and the bases for clinical diagnosis.

DCLD has also issued a general guidance document on the conduct of IVD clinical trials which should be reviewed by sponsors prior to conducting such trials. Entitled "Points to Consider for Collection of Data in Support of In-Vitro Device Submissions for 510(k) Clearance," it covers study protocols, sampling methods, study site requirements, product inserts, and the responsibilities of principal investigators of clinical trials.15 This guidance document has not been finalized and contains several controversial provisions, including the requirement that the investigator sign off on the study, indicating that he or she has reviewed and verified the data and the manufacturrer's presentation of the data analysis to FDA. Nevertheless, this guidance is helpful in evaluating how DCLD looks at the important clinical issues for IVD trials.

Finally, for IVDs and all other devices, the issue of demonstrating clinical utility as well as safety and efficacy should not be overlooked. FDA has recently been placing a greater emphasis on demonstrating clinical utility in device trials, much to the consternation of the device industry.

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