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ne doesn’t expect to see an elephant in the meeting room of the FDA’s Orthopedic and

Rehabilitation Devices advisory panel. But there it was.

It took Howard Gill, M.D., president of the American Orthopaedic Foot & Ankle Society, to point out the elephant in the room as the panel met on April 24, 2007, to decide whether to recommend approval of Link USA’s Scandinavian Total Ankle Replacement (STAR) pre-market approval (PMA) petition.

In the end, the panel voted 4-2 to recommend approval with conditions.

The STAR device is a first-of-its-kind non-constrained, mobile-bearing ankle prosthesis intended for use as a

non-cemented implant to replace an arthritic and/or severely deformed ankle due to rheumatoid arthritis, primary arthrosis, or posttraumatic arthrosis.

Some consider ankle replacement devices an orphan device because of their relatively small market. According to Link’s CEO, Andy Greenberg, there are approximately three to four thousand procedures in the U.S. per year, with an average cost of $8,700 to $9,500 per procedure.

If the panel’s recommendations are followed by the FDA, patients in the U.S. will get to join the rest of the world in having access to a three-part mobile-bearing ankle arthroplasty technology. This technology has been used throughout the world for more than a decade. Futhermore, if approved, the STAR device will be the first ankle in the U.S. that can be used without cement on-label.

Total Ankle Replacement Background

Total ankle replacement has been investigated since the 1970s with initially promising results, but the procedure was essentially abandoned in the 1980s due to a high long-term failure rate, both in terms of pain control and improved function.

However, researchers have continued to investigate new designs, which can be broadly subdivided into constrained and unconstrained designs.

Constrained prostheses offer the advantage of greater stability, but with decreased mobility and increased stress at the bone implant interface, potentially leading to a greater risk of early loosening and failure.

Unconstrained designs provide improved range of motion in multiple planes, but at the expense of stability. The first

FDA Ortho Panel Recommends STAR Ankle PMA Approval—With Elephant in the RoomBy Walter Eisner

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The STAR

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devices investigated were implanted with cement fixation, which in recent years has given way to cementless designs.

Currently, four ankle prostheses are commercially available or under investigation in the U.S.: the Agility Ankle, the Topez Total Ankle Replacement System™, the STAR device, the Buechel-Pappas device, and the TNK ankle. The STAR device, the Buechel-Pappas device, and the TNK ankle are not currently approved by the U.S. FDA.

The STAR design uses a unique three-piece system. One piece of metal fits into the tibia, the thicker of the two bones in the lower leg. Another metal piece fits into the talus bone of the ankle. A piece of polyethylene plastic floats between the two metal pieces

The elephant in question was that the FDA had previously approved two-part total ankle replacements as Class II devices. Link’s three-part device was being subjected to the rigorous and expensive trial requirements demanded of Class III devices.

In May 2002, the FDA cleared the Agility Ankle Revision Prosthesis, which is intended for cemented use only in patients with a failed previous ankle surgery. Agility received FDA clearance for marketing through the 510(k) process, and thus detailed clinical outcomes were not required for FDA approval.

In November 2005, the FDA cleared DePuy’s Topez Total Ankle Replacement System™ as being substantially equivalent to the Agility model and with the same indications for use.

So we have two types of ankles, two-piece and three-piece designs, each requiring a different regulatory pathway.

Glenn Stiegman, the former chief of the Orthopedic Devices Branch for the FDA, and now VP of regulatory affairs for Musculoskeletal Clinical Regulatory Advisors,

told us that the distinction between the Class II and Class III total ankle replacement can be a little complicated. Says Stiegman, “It is the amount of constraint and mobility that really determines the class of ankle. The STAR Ankle has two articulating surfaces [one on either side of the polyethylene bearing] which allow non-constrained anterior/posterior, and medial/lateral translation as well as rotation.

In order to have this mobility, its design consists of three components.

On the other hand, DePuy’s Agility Ankle, a Class II device, also consists of three components, but only one articulating surface. However, based on the manner in which the tibial component and polyethylene bearing are fitted together, the Agility only allows limited anterior/posterior and medial/lateral translation and rotation. This similar scenario also exists in the knee market where semi-constrained knees that allow anterior/posterior movement and rotation are Class II. In Class II knees, the polyethylene bearing is snap-fit to the tibial tray to allow only one articulating surface between the tibial and femoral components.

The Class III mobile bearing knees are essentially unconstrained with two articulating surfaces, and most often have three components to achieve this. These distinct regulatory pathways, 510(k) vs. IDE [investigational device exemption] and PMA, were mainly brought about by what was on the market before 1976, as opposed to where the patient, surgeon, and technology have taken us since then, which is allowing the device and patient to have more mobility.”

Dr. Gill’s point was to bring to light that somewhat small device variations constitute a rather easy pathway to market compared to a very burdensome, costly, and time-consuming pathway to market.

“In fact,” says Stiegman, “this small distinction can drive technology or stagnate it in this case, simply because of the regulatory process. This is one of those unfortunate situations where it is unknown whether those ankles that have that extra mobility are better than those that have more limited mobility and an easier market pathway. Until the lack of constraint for these total ankle replacements

The Buechel-Pappas

The Agility

The Topez

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can be characterized using special controls other than clinical data, that small difference will still place these devices into the IDE and PMA pathway.”

The Data

Link and FDA presentations focused on clinical data collected on the device, which has been implanted in more than 600 patients in the various arms of the study.

“This is a culmination of a seven-year pre-marketing approval study,” Michael J. Coughlin, M.D., a co-investigator for the STAR device told the panel.

The clinical data were collected in a non-randomized, multicenter study intended to demonstrate the device’s non-inferiority to a control arthrodesis treatment. Patient success was defined as a 40-point increase from baseline on the Buechel-Pappas (BP) Pain Scale, while the safety composite success consisted of no device failures, revisions or removals, radiographic success, and no major complications. The STAR System study results were found to be non-inferior to the arthrodesis control.

Coughlin, Charles Saltzman, M.D., and Roger Mann, M.D., presented two-year follow-up data for a trial comparing total ankle arthroplasty using the STAR system to ankle arthrodesis. The results showed diminished pain, improved function and continued range of motion with the three-part total ankle that includes a mobile bearing.

At 24-months follow-up, the patient success rate was 13.7% for controls vs. 45.1% for the STAR group. Also, the efficacy success rate was 14.9% for controls vs. 58.5% for the STAR group and the safety success rate was 82.7% for controls vs. 71.1% for the STAR group, according to the executive summary provided to the committee by Link Orthopaedics.

At 12 months, Buechel-Pappas scores averaged 65.9 points for controls vs. 80.7 points for STAR patients. At 24 months, scores averaged 69.7 points for controls and 81.6 points for STAR patients, according to Link’s executive summary.

Panel Deliberations

From there, the panel deliberations went as they usually do these days at FDA panel meetings. After the sponsor’s data is presented, FDA statisticians inevitably cast doubt on the quality and validity of the sponsor’s evidence. The FDA can usually shoot holes in the sponsor’s study because no clinical studies are perfect.

In this case, the FDA attack focused on the point that Link had revised the pivotal radiographic analyses that were initially performed in the PMA. These revised analyses impact a total of 12 patients:

• Seven patients who did not meet the original analysis definition of success at 6 or 12 months and who were radiographic successes at 24 months, but were carried forward as radiographic failures, and

• Five patients who were radiographic failures, but who were considered clinical successes.

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Panel member Michael Mayor, M.D., a professor from Dartmouth, expressed great “disappointment” with the testing done on the polyethylene components of the device and minced no words in his opinion that the testing consultant hired by Link was not adequately informed of the most up-to-date testing protocols in the field. While acknowledging that arthroplasty is the most cost-effective treatment for all joints, he voted against approval of the device with a warning that there could be catastrophic failures for patients.

Kathleen Propert, Sc.D., a biostatistician from the University of Pennsylvania, said that the sponsor’s data did not meet her requirements of statistical certainties and also voted against approval.

Positive Recommendation and Conditions

The orthopedic surgeons on the panel acknowledged that the data wasn’t perfect, but that the concerns about the revision in the radiography analysis were not statistically significant and voted for approval with conditions.

The recommended conditions of approval were:

1. There should be a postapproval clinical study with independent radiographic assessment to evaluate the long-term safety and performance of the ankle prosthesis.

2. There should be an update to the surgical manual to reflect modifications not yet implemented but described by the applicant.

3. There should be preclinical studies to validate the applicant’s proposed weight limit.

4. There should be patient education to describe the warnings contained in the package insert in laypersons’ terminology.

5. “Severely deformed” terminology should be removed from the indications for use, and “primary arthrosis” should be replaced with “degenerative arthritis” in the indications for use.

Andy Greenberg, president of Link Orthopaedics, said, “We would like to thank the incredibly talented and dedicated team of clinicians that willingly gave their time and efforts to work to improve patient outcomes in the United States, to produce the most comprehensive study in the history of foot and ankle surgery.

The orphan device was adopted this day, but the elephant remains and we’ll have more to report on this in upcoming issues.