FzioMed (San Luis Obispo, California) may have bombed at the 2008 advisory hearing for the company's Oxiplex hydrogel for spinal surgery, but the company and FDA are headed for a June 10 hearing at the dispute resolution panel. FzioMed's President/CEO, John Krelle, told Medical Device Daily that three of the members of the 2008 advisory will appear at the dispute hearing in support of the application, and that the device now enjoys the implicit support of four appearances in the peer-reviewed literature, which Krelle said would go a long way to help make the company's case.
The application had to overcome several obstacles at the 2008 advisory, including that efficacy data were uneven across the pivotal study cohort, and the use of a multivariate analysis that was not included in the original study plan seemed to sway few, if any panelists (MDD, July 17, 2008). This post-hoc analysis indicated that patients undergoing spinal decompression surgery had better outcomes with the use of the anti-adhesive agent assuming they reported back pain at baseline, but the application fell on a 5-2 vote against approvability.
Krelle said "a lot more clinical evidence has come to light" on the question of preoperative back pain. He said "it is well known that higher levels of pain, particularly in the back, will get you worse results" for these procedures.
"We've had many meetings with [FDA] since 2008," Krelle remarked, including to discuss a narrowing of the indication to those with back pain at baseline. Despite the concession on the labeled indication, "they still require more and more data," he said, which the company supplied via two outside-U.S. (OUS) studies that confirm efficacy in this subgroup. Krelle also observed that Spine is among the publications that have featured articles on the device, adding, "I think the data have gained a lot" of credibility.
Krelle indicated that clinicians' understanding of the role of back pain has changed since 2008, and he said reviewers at the orthopedic devices branch "have approved many devices using post-hoc analyses" despite the agency's criticism of the analysis employed by FzioMed. A factor Krelle said might render a more objective ruling is that "with the dispute resolution panel, there are three standing members and four ad-hoc members," and that between this and the format of the hearing, it will be "more like a trial by jury" than is the case for typical advisory hearings.
Krelle said the number of OUS uses of the device has swelled from 100,000 in 2008 to more than 350,000, and noted that the four published studies "are all randomized, blinded trials."
When asked about clinical acceptance, Krelle said a "large team" of spine surgeons will represent FzioMed at the hearing. "They all believe as we do that there is this group of patients who will benefit. We even have three former panel members from 2008" standing up for the company in June, he said, adding, "under the rules of the game, this product should be approved."
Krelle said the company fields queries about the device's availability from spinal surgeons at medical society meetings. "We go to NASS every year," he said of the annual meeting of the North American Spine Society (Burr Ridge, Illinois), adding, "people beat a path to our booth" to ask why the device is not available. Meanwhile, "FDA sits by and allows spine surgeons to use amniotic membranes" and other tissues to deal with adhesions, uses that he said are backed by no data.
FDA cites 'data integrity' in warning
Few things excite regulators more than something suggestive of fudged data, and the April 1 warning letter to LumiQuick Diagnostics (Santa Clara, California) reflects those concerns. The first two citations in the warning deal with device design and design controls, and the agency capped off both with the statement: "If the data was not gathered at the time of the initial study, your addendum may raise data integrity concerns.
The February inspection of the company's plant in Santa Clara addressed the company's manufacture of test cards for a number of disease states, including Malaria and several cancers. The first citation states that a November 2013 internal report states that 14 of 66 tested units "did not function," with a dozen of these yielding "no results." The agency stated further that each of the 24 units tested "at the lower limits . . . gave faint lines," but that LumiQuick nonetheless "concluded that the study was successful."
The report in the design history file is said to have indicated 100% sensitivity and 100% specificity, but FDA asserted that the underlying data did not support a conclusion "of meeting the written user requirements."
LumiQuick is said to have promised to "review design history files of all products and conduct additional studies as needed," and to revise the related SOPs. However, FDA said it could not determine the adequacy of this response because the company did not include copies of the revised procedures "or other evidence of corrections." The company also indicated it would append data on the 12 no-result tests to the Malaria test's files, but FDA remarked at this point on the data integrity dilemma created by the inclusion of data "not gathered at the time of the initial [validation] study."
The second citation makes reference to an "undated report and summary validation" addressing a change to the buffer volume used to test Malaria antigen. FDA alleged the report "indicates that [the company was] aware of Malaria antigen tests failures," and that LumiQuick "made a change to the volume of buffer required for the assay . . . and used this report to justify the change in the labeling." The FDA investigator asked for data to support the change, at which point the company is said to have "produced a laboratory notebook page for an unrelated buffer test with different dates, different product lot number and none of the data referenced" in the Malaria test documentation.
For this citation, too, LumiQuick indicated it would draft "a memo to the file to add information about the missing acceptance criteria," the warning letter said, but FDA again remarked on the consequent question about data integrity.
LumiQuick did not respond to contact for comment.