Medical Device Daily Washington Editor

WASHINGTON — The job of coming up with clinical endpoints for a clinical study of a truly novel device is always problematic. Add the reluctance of enrollees to be control group participants and a manufacturer must overcome considerable anxiety by FDA reviewers.

The experience of the Corin Group (Cirincester, UK), in its effort to get its Cormet 2000 hip resurfacing system into the U.S., runs along these lines, with the FDA's orthopedics and rehabilitative devices panel grappling with the lack of a control group at its meeting last Thursday.

Though hip resurfacing is an invasive procedure, it is less invasive then total hip replacement, and so it was difficult for Corin to develop a total hip replacement control.

This was the basis of the FDA's reservations, but the panelists — having more real-world practice — appeared more flexible, voting 4-1 to recommend approval.

Ian Paling, Corin's CEO, told Medical Device Daily , "we didn't realize at the time" of trial launch that subjects would not be interested in enrolling in a control arm — requiring total hip replacement — because more invasive.

Also, for younger patients, the less-traumatic hip resurfacing also leaves the option of a total hip replacement at some later point.

In 2001, when Corin obtained conditional approval for its study protocol and started enrolling subjects, Stryker (Kalamazoo, Michigan) was still conducting its study of its ceramic-on-ceramic hip resurfacing products and no results were available for any metal-on-metal products at that point. When the Stryker data did come out, Corin suggested that the trial be tweaked to accommodate those findings, which took place in 2003.

An additional complicating factor was that "potential radiographic parameters of success and failure were identified in the literature after enrollment," according to Bernard Stulberg, MD, of the Cleveland Orthopedic and Spine Hospital, part of the Cleveland Clinic (Cleveland Ohio), speaking on the sponsor's behalf. When such data appeared in the medical literature, the company's parameters proposed for radiographic indices turned out to be more demanding than anything published by practicing physicians.

Among the parameters that the company amended in its Cormet application was that of radiolucency during X-ray exams, the appearance of visible space between the ball and the socket components of the device. One of the initial criteria was "no new or progressive radiolucencies" of greater than 1 mm.

The revised criterion, which Corin said was more in line with the literature, was no new complete radiolucencies "in all three zones," a reference to a division of the lateral image of the ball and socket into three equal portions totaling approximately 180 degrees.

A similar adjustment was made to the tolerances for shifting of the ball component of the device where it is inserted into the femur.

Richard Mott, MD, president/CEO of Wright Medical (Arlington, Tennessee), speaking for the sponsor, said, "I'm coming here as someone who has done a lot of resurfacing," totaling about 1,200 such procedures over the past 18 years. He said of those, "about 650 resurfacings were of metal-on-metal," adding that "all these resurfacings are fairly similar, and if you approve one, you have to approve them all."

"We had a tremendous learning curve experience with Wright Medical," Mott said, including a number of fractures, which led to an investigator meeting. When Wright changed the indications to exclude those with substantial body mass indices and osteopenia, the fracture rate dropped from 17% to about .2%.

"My main message is to urge education. I believe that if companies . . . urge surgeons to use the appropriate procedures . . . you can reduce these complications to a very low level." Mott said that it is up to the companies to enforce educational requirements and that each surgeon's first five procedures should be monitored.

Thomas Schmaltzreid, MD, associate director of the Joint Replacement Institute (Los Angeles), supported the company's argument that patient selection for the control group was difficult. Patient selection, he said "has truly evolved," partly because some reports indicate that short-term, femoral neck fracture is more common among women, and because age and gender "are surrogates for bone density."

"When I select patients, I try to pick winners, for lack of a better term," Schmaltzreid said.

He noted also that the Internet blunts the prospect of enrolling subjects in control study arms. Because of the volume of information available online, "[t]he level of pressure coming from the patients" is driven partly by perception of benefits with sometimes little regard for risk, he said.

Elizabeth Frank, lead FDA reviewer, noted "multiple revisions to primary safety and effectiveness endpoints" in the study, but she also acknowledged that a comparator control group was difficult to come by.

Frank expressed concern over the poor outcomes of some resurfacing procedures in the trial, pointing out that patients in the lowest quartile of Harris hip scores were more than six times more likely than others to have to undergo a surgical revision. But her biggest complaint was that "the changes made to the protocol . . . all weaken the validity of this study."

Early in the discussion, Michael Mayor, MD, professor of orthopedics at Dartmouth Medical School (Hanover, New Hampshire), said, "efficacy endpoints appear to have been maintained in a reasonable manner" but the change from a concurrent to historical controls constituted "a near-tragic compromise" of such requirements. He also argued that the changes to various criteria for outcomes "optimized the chances for success."

Harry Skinner, MD, a professor of orthopedics at the University of California Irvine Medical Center, said protocol changes were not "optimal, but I think we have to be pragmatic" about the difficulty of control group recruiting.

The vote followed a discussion of potential changes to the firm's proposed follow-up study, then choosing to let the agency and Corin work out details.

A check of any metal residue in the blood was also part of the discussion, but between procedural issues and the improbability of designing a study on the fly in such a short span of time, the panel decided that the effort was beyond their resources.

The agency does not have to follow the recommendation, but if the Cormet is approved, it will enable Stryker (Kalamazoo, Michigan) — which will market the product in the U.S. — to compete with Smith & Nephew (London) in this technology sector.