The US Food and Drug Administration’s (FDA) Center for Devices and Radiological Health (CDRH) on Monday raised key questions about the effectiveness of Cartiva’s first-of-its-kind synthetic cartilage implant, which is intended to treat osteoarthritis pain in the first joint of the big toe.
The implant, which is made of an organic polymer-based biomaterial comprised of polyvinyl alcohol and saline, is designed to work in a manner similar to how biologic cartilage works, but it’s intended to help with damaged cartilage and to allow for pain reduction and maintained range of motion.
The Orthopaedic and Rehabilitation Devices Panel of the Medical Devices Advisory Committee, a panel of outside experts, will listen to both Cartiva and FDA officials explain what they saw in the company’s clinical trial of the implant at a meeting Wednesday.
In briefing documents released before the meeting, FDA raised a number of questions about Cartiva’s non-inferiority trial, which was conducted in Canada and the United Kingdom on patients with osteoarthritis, which is the most widespread type of arthritis or joint disease.
Clinical Trial Questions
Although the trial for this pre-market approval application was conducted outside the US, FDA makes clear up-front that some of the clinical study design issues raised by the agency in preliminary feedback were ultimately incorporated into the study protocol and adequately addressed by Cartiva, though “at the time of PMA submission, others were not.”
The trial compared subjects treated with the Cartiva implant and whether they would have a non-inferior response when compared to those having the conventional treatment of fusing the first metatarsophalangeal joint.
In its review of the PMA, FDA raises concerns related to the time of the study endpoint (which was pushed back by FDA from 12 months to 24 months), differences in success criteria for each group, and, among other details, whether the 15% non-inferiority margin is clinically appropriate.
“If, for example, a lower non-inferiority margin of 10%, corresponding to that typically utilized in non-inferiority studies for other orthopedic implants, were to be utilized for the evaluation, then both the pre-specified and post-hoc primary composite endpoints would not be met for this study,” FDA says. “Whatever non-inferiority margin is utilized, FDA believes this margin should correspond to a maximum clinically insignificant difference for the investigative and control treatments.”
However, FDA acknowledges that the clinical study appears to demonstrate that the Cartiva subjects “experienced increased maintenance range of motion while experiencing lower reductions from baseline VAS [Visual Analog Scale] pain scores as compared to Arthrodesis at 12 and 24 months. The benefits and risks of this device have been identified.”
But the agency concluded that in light of remaining questions about the “clinical justification of the non-inferiority margin, primary endpoint data assessment, and adverse event profile, a determination of the relative weight of the benefits and risks of the device remains unclear.”
Wednesday’s panel will include three voting questions for the panel of experts:
1. Is there a reasonable assurance that the Cartiva Synthetic Cartilage Implant is safe for use in patients who meet the criteria specified in the proposed indications for use?
2. Is there a reasonable assurance that the Cartiva Synthetic Cartilage Implant is effective for use in patients who meet the criteria specified in the proposed indications for use described above?
3. Do the benefits of the Cartiva Synthetic Cartilage Implant outweigh the risks when used in patients who meet the criteria specified in the proposed indications for use described above?
The agency also asks the panel to discuss the 15% non-inferiority margin used for the Cartiva clinical study, as well as how to evaluate the fact that prospective subjects will likely have the impression that increased mobility will allow for greater function in Cartiva as compared to Arthrodesis treatment, even though “the level of function for Cartiva appears to be the same or worse than Arthrodesis from 3 months to 2 years.”
20 April 2016 Meeting Materials of the Orthopaedic and Rehabilitation Devices Panel