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This article was originally published in The Gray Sheet

Executive Summary

The existing clinical data on use of detachable silicone balloons for the therapeutic occlusion of cerebral vessels fails to support safety and effectiveness, FDA's neurological devices panel concluded at a June 11 meeting in Rockville, Maryland. The panel reviewed almost four years of clinical information, including data collected by Interventional Therapeutics Corporation pursuant to an investigational device exemption. FDA terminated ITC's investigational device exemption for the DSB in March 1992 on the grounds that the firm had distributed 400 more devices than had been authorized ("The Gray Sheet" April 27, 1992, p. 3). The panel also considered data from the literature and from studies of a Becton Dickinson device. The panel was convened to consider whether existing data on this type of balloon therapy provides "valid scientific evidence of safety and effectiveness" for any indications. The panel, focusing primarily on the ITC data and citing poor study design, lack of appropriate controls and inadequate followup, determined that it does not. Since FDA revoked ITC's IDE, the company's detachable balloon has been available only on a case-by-case basis under the agency's emergency use policy. The agency sent a letter to hospital institutional review boards on March 11 reiterating its position vis a vis the device: "distribution of this device is not approved by [FDA] as required by law." The letter notes that without a new IDE from ITC or some other interested party "sometime in the near future, FDA will need to re-evaluate the impact of emergency use" on patients. The DSB is being used by clinicians in a number of different situations, according to presenters at the meeting. For example, clinical investigator Randy Hagashida, MD, University of California, San Francisco, discussed use of the balloon "in the treatment of carotid cavernous fistulas...treatment of inoperable or otherwise untreatable cerebral aneurysms...and third for presurgical occlusion of the carotid artery for the control of hemorrhage in association with the surgical management of neoplastic tumors of the skull base and neck." According to Hagashida, candidates for the therapy in ITC's clinical study included patients who were "neurologically symptomatic with failed conventional forms of medical or surgical therapy or who were...poor surgical candidates due to underlying medical condition and who lacked alternative therapies." Levering Keely, a senior scientific reviewer in FDA's office of device evaluation, division of cardiovascular, respiratory and neurological devices, asked the panel to address a number of concerns about the DSB balloon, including consistency of clinical data, controls and followup. ITC initially submitted clinical data on the device in the fall of 1992, Keely said, making a second submission in April 1993 that " a compilation or stratification of the data presented earlier." The April submission, Keely noted, did not appear consistent with the earlier data. For example, "the data presented in April 1993 fails to include many patients who have previously been identified in other submissions and appear otherwise eligible for reporting in this submission. Numerous patients appear to have had less than desirable outcomes which required other intervening treatment who were not included within the submission." Company consultant Glen Rahmoeller, Biometric Research Institute, responded that ITC "submitted [the April] data in a reformatted format to make it easier for FDA to analyze...and we did that on the first 380 procedures." He added that the firm is "in the process of submitting the remainder of the procedures to FDA." Keely also raised the question of controls. While the study included some historical data from the literature, Keely said "there was no identified, well documented population of historical controls." Also, "no in-depth analyses of any historical controls with similarity to this population occur, and there is no way that you can tell whether the historical controls had the same characteristics as the...patients included in the study." Keely concluded that "after review of this data, [FDA] can't concur with the sponsor's results." Hagashida earlier had told the group that device success was defined as balloon positioning without technical problems, while procedure success "was defined as occlusion without technical procedural complications." Clinical success was defined as "the patient stabilized or improved following treatment." Among individual presenters at the meeting, investigator Philip Purdy, MD, Southwestern Medical School in Dallas, reported that of 179 procedures treating carotid cavernous fistulae, the overall device success rate was 92.7% and the procedural success rate was "in excess of 92.7%." Stan Barnwell, MD, Oregon Health Sciences/University in Portland, said that a study of 152 patients with inoperable intracranial aneurysms yielded a 97% procedure success rate and 95% clinical success. However, despite the high reported success rates, advisory panel member Harold Wilkinson, MD, PhD, University of Massachusetts Medical School, Worcester, said that the study had "such limited short term...followup [and] no long term followup greater than six months" that he could not "see how any claims of safety and efficacy are valid," or "how you can have a basis for comparing this technique with any other technique." Wilkinson also criticized ITC's definition of clinical success, describing it as "not at all precise." For example, he asked, if after a procedure with the device, "relief of symptoms or simply an imaging study showing initial total occlusion prevents that patient from undergoing alternative surgery, even though the alternative surgery might be risky, and the patient later dies, is this a bad outcome or a good outcome? The patient died. The hemorrhage might have been delayed by the balloon." He concluded that this is "a very shady area...and some definition needs to be included in the data." Adding to the comment on the clinical success parameter, Leslie Francis, University of Utah College of Law, Salt Lake City, a special consultant to the panel, noted that "the issues of subjective versus objective definition of success are very troubling in the different classes of patients." For example, she said that if the data resulting from the management of the patients in ITC's study was compared with data from groups managed using other therapies, "we don't really know from this data whether these patients' outcome numbers look worse or better than ...other groups might look." Panel member Frank Yatsu, MD, University of Texas, Houston, said that although he "was very impressed by the presentation and [could] understand some of the clinical situations where balloons can be useful," he believed that the firm still needs to "solidify the evidence regarding safety and efficacy." Specifically, he noted that the issues of "adequate control and...the completeness of data" needed to be addressed. Mark Wholey, MD, University of Pittsburgh, commented that "this technique has a lot of merit, and if you take just... acute technical success [the presenters] have impressive numbers." However, he asked: "Was the study well designed? No." He added that he believed further study of the device "could be done very easily, and I think it probably should be done in a significant trial."

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