FDA Staff Still Skeptical of Plastic Meniscus Replacement

Technical staff at the FDA said they were unsure whether the benefits associated with an investigational meniscus replacement product outweighed the risks, citing substantial rates of poor clinical response and adverse effects in a clinical trial.

Called the NUsurface Meniscus Implant, the device will be discussed at an FDA advisory committee meeting on Thursday. A briefing document prepared by agency staff to summarize the available evidence was released early Tuesday.

The product is a semi-soft plastic disc intended for patients with persistent knee pain following medial meniscectomy. "Meniscus replacement has the potential to fill the gap between minimally invasive meniscus repair and total knee replacement," according to the manufacturer, Tennessee-based Active Implants. The company further explained that the product is made of polycarbonate-urethane and "does not require fixation to bone or soft tissues"; it is simply inserted into the medial compartment and is held in place by the joint's natural shape.

At least initially, most patients who still experience significant pain after meniscectomy are given non-opioid painkillers, steroids, hyaluronic acid injections, and/or physical therapy, and may be urged to lose weight as well. Surgical options include meniscal allograft transplant, resorbable scaffold implants, and unloading osteotomy, FDA staff noted.

The NUsurface implant has been available in Europe for 15 years, and Active Implants has been going back and forth with the FDA over that same interval. The current application represents Active Implants' fifth attempt to get the product onto the U.S. market.

It initially sought a simple 510(k) clearance, saying the product was substantially equivalent to metallic spacer devices then in use, but twice the agency said no. Eventually Active Implants agreed to pursue authorization under the agency's "de novo classification" pathway for novel devices considered to be relatively low risk. That was in 2014. Two "de novo" requests were denied, the first because it lacked clinical data. The company then conducted two clinical trials (one randomized and one single-arm, with a total of about 300 patients) to support a revised request, but that too was rejected "due to the large number of device failures and unmitigated risks that raised uncertainty about the benefit-risk profile as well as the clinical safety of the device," FDA staff recounted.

Active Implants has now narrowed the proposed indications to cover only those patients who would benefit more from the NUsurface implant than conventional approaches without increasing risks. As stated in the briefing document, they are:

• Mild-to-moderate osteoarthritis of the knee
• Mild or greater knee pain
• Cartilage present on the load-bearing articular surface

Additionally, Active Implants proposed 17 contraindications, meant to weed out patients at highest risk for unsuccessful outcomes. Besides the usual ones like allergy to device components, they included:

• Bony lesions in the joint that would contact either the femoral or tibial side of the device
• Abnormal knee laxity
• Medial meniscus extrusion 5 mm or greater
• Greater than 5° loss of extension and greater than 15° loss of flexion difference between index and contralateral knee, or extreme varus/valgus alignment between tibia and femur
• Abnormal cartilage shapes or bone deformities in the joint

And the company offered to include warnings about other factors that increased the likelihood of poor outcomes, such as tibial spine heights less than 11 mm and BMI values above 32.5.

Nevertheless, FDA staff indicated that they remained unsure whether Active Implants has succeeded in mitigating the risks of adverse events.

Two factors drove their uncertainty. First, 38% of patients who rated their own pain and function said they didn't see clinically relevant improvement. Second, adverse events were far from uncommon.

The briefing document noted that 17% of patients required a second surgery within 2 years, and 12.5% "experienced noises including clicking, popping, and squeaks, which may portend device-related mechanical integrity or positioning issues."

In all, 42% of patients receiving the device experienced serious adverse effects, as compared to 13% of non-surgical control patients in the randomized trial. In the NUsurface group, these mostly related to the device itself: rotation, migration, and tearing. As well, 13% of NUsurface recipients had problems with restricted motion, which was not seen in any control patient.

Staff also pointed to problems with the trials' methodologies, including "a large percentage of missing data in the non-surgical control arm," and with patient preference surveys conducted by Active Implants. The latter had indicated that patients would gladly accept the device, but, according to the briefing document, they "do not align with accepted preference-based, good research methods" and thus "did not provide a useful measure of the value of treatment relative to the alternative."

Members of the FDA Orthopaedic and Rehabilitation Devices Panel of the Medical Devices Advisory Committee will be asked to vote on whether they think the implant's "probable benefits ... outweigh the probable risks" when used according to label instructions. They will also be asked to give opinions on interpreting the trial results, the most appropriate patient population and selection methods, the importance of revision surgeries in assessing the risk-benefit balance, and the clinical practicalities of evaluating patients for such factors as meniscal extrusion and tibial spine heights.

The FDA is not required to follow its advisors' recommendations, but it usually does.

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