FDA Denies FzioMed PMA

“We regret to inform you that your PMA (premarket approval) application is denied.”

With those words on October 21, 2013, the FDA notified John Krelle, the president and CEO of FzioMed, Inc. that his company’s Oxiplex Gel product will not be allowed in the U.S. The agency posted the letter on their website on February 10, 2014.

Regulatory Gauntlet

FzioMed filed their PMA application in August 2007. The agency’s orthopedic panel met in July 2008 and voted to recommend against approval. The FDA then issued “not approval” letters in September 2008 and once again in January 2010. In October 2011, the company requested supervisory review by the Office of the Center Director of the not approvable decision. A letter issued on October 9, 2012, by William Maisel, M.D., on behalf of the Office of the Center Director, upheld the not approvable decision.

The company then chose to exercise the option to consider the October 9, 2012 decision letter to be a denial of approval of the PMA and requested an administrative review by filing a petition for reconsideration on November 5, 2012. On November 4, 2013, the company announced that FDA Commissioner Margaret Hamburg, M.D. approved their petition for an independent review of their PMA and a special Medical Devices Dispute Resolution Panel was convened. Then came the letter of denial.

According to the company, no jurisdiction other than the U.S. has ever denied an application for approval of Oxiplex, which has been available outside the U.S. for more than a decade. It is approved in 70 countries including the 28 member states of the European Union, The Russian Federation, Canada, and Mexico, as well as on the Continents of Africa, Australia, South America and Asia.

Letter of Denial

The letter of denial identified the reasons for denying the PMA and identified the measures necessary to make the PMA approvable. “In summary, ” stated the letter, “you have not provided a reasonable assurance of the safety and effectiveness of the device under the conditions of use prescribed, recommended, or suggested in the proposed labeling.”

The agency said additional confirmatory clinical evidence of device performance is needed to establish a reasonable assurance of the effectiveness of the device. The letter noted that the company’s U.S. pivotal study failed to show a statistically significant and clinically significant difference in the overall treatment effect for Oxiplex.

The letter also noted that the FDA’s orthopedic panel raised questions related to the safety of the device in the intrathecal space as well as the effect of the device on osteoid activity and local cytokine release. “You stated at the panel meeting that there are primate data and other ongoing studies that would address these concerns. However, to date, you have not provided these data to FDA for review, ” continued the letter.

FDA Requirements

The agency offered advice to the company when submitting further evidence in the form of additional clinical data that show a statistically and clinically significant treatment effect in the relevant patient population.

“The data may be from one multiple-arm study or from two separate studies, and should use a primary effectiveness endpoint of mean reduction from baseline pain to 6 month post-operative residual pain using a validated pain scale. To provide evidence of a reasonable assurance of effectiveness to support both or either indications, the study(ies) should demonstrate in the relevant patient population a statistically and clinically significant result of at least a 10% difference in the primary effectiveness endpoint, in favor of Oxiplex, when the mean difference between the groups is divided by the treatment effect in the control group. This assumes at least a 50% reduction in baseline to 6-month residual pain in the control group. Other primary effectiveness measures may also be acceptable. If you plan to leverage any prior clinical data, we encourage an assessment of the final device formulations to ensure comparability across important specifications.”

According to the company, Oxiplex was studied in two U.S. FDA-approved Investigational Device Exemption (IDE) clinical trials, as well as two foreign confirmatory clinical studies in subjects undergoing spine surgery. The IDE pivotal study, which required more than five years to complete, found that subjects having both leg pain and severe preoperative back pain experienced a greater reduction in leg pain when treated with Oxiplex compared to undergoing surgery alone.

“The extensive body of peer-reviewed published literature on Oxiplex, as well as extensive commercial experience outside the U.S. in more than 340, 000 surgeries, provides additional evidence of the safety and effectiveness of the device for use in conjunction with spine surgery, ” stated a company press release last November.