Medical Device Daily Washington Editor
GAITHERSBURG, Maryland — Several recent FDA panel hearings for medical devices have resulted in margins of victory for sponsors so decisive that the description "slam-dunk" would not seem inappropriate. Thursday's hearing of the obstetric and gynecological devices advisory committee likewise resulted in near landslide approval, despite three dissenting votes in the end.
Last Thursday's hearing was for the Adiana contraceptive device, which Hologic (Bedford, Massachusetts) acquired in its $6.2 billion purchase of Cytyc (Marlborough, Massachusetts).
However, the news for industry may seem a bit mixed because FDA seems to be ratcheting up the requirements for post-approval studies (PAS), giving device makers increasing reason to ask whether devices that promise thin profit margins will still be profitable.
At present, the market for sterilization devices is held by two clip-like devices and by the Essure, manufactured by Conceptus (Mountain View, California). The Essure, made of coiled metal, is the only other implantable tubal blockage device currently having PMA approval (November 2002).
Ted Anderson, MD, a professor of obstetrics and gynecology at the Vanderbilt University Medical Center (Nashville, Tennesse), described the Adiana as a matrix of silicone and rubber implanted into the fallopian tubes at the uterine juncture, with the site of the implant having to be ablated with RF energy prior to placement to ensure binding.
Anderson, the pivotal trial's principal investigator, said that "of the 645 patients in the intent-to-treat group, 95% had successful bilateral placements," at the time of surgery. "The procedure is very straightforward," he said, adding that "90% of these procedures were performed in less than 20 minutes." He said that "about a third of the patients required no sedation."
"There were no unanticipated procedural adverse events," Anderson said, and that the study included no uterine perforations. He said that 98% of the women returned to normal activities within two days. At one week, 551 of the 604 patients had bilateral occlusion of the fallopian tubes at one week, and another 19 of the remaining 53 achieved bilateral occlusion at their three-month check-ups. Hence "94% were able to rely on this device for contraception" within a quarter year.
The study population experienced six pregnancies in the first year, three adjudicated as misinterpretations of radiographic examinations, the other three considered device failures "of undetermined cause," Anderson said. He noted that "the cumulative failure rate [at one year] was 1.07%," exceeding the primary efficacy endpoint of 5% at one year.
Amy Pollack, MD, of Columbia University School of Public Health (New York), the former chief medical officer at Adiana - the company that originated the device — discussed the unmet need for sterilization, saying that for women of childbearing age, "[b]alancing safety and efficacy while managing sexual relations is difficult."
She said, "the pill is the most commonly used method in the U.S. despite a failure rate of almost 8%." Intrauterine devices have a failure rate of about 3%, Pollack said, but are chosen by only 2% of those who seek contraception.
The Adiana device requires the use of hysteroscopy, which is associated with uterine perforation, but Pollack said that this risk is based on previous methods of hysteroscope deployment not pertinent to the Adiana. She added that the sponsor saw "no adverse device reactions" after 16,000 wearer months.
Glenn Bell, PhD, a biomedical engineer and lead agency reviewer for the device, told the panel, "there were several changes to the device, including a change to the handle on the ablator actuator from a thumb slide to a push-button actuator. There were also changes post-trial, but Bell said "it is believed that none of these changes will affect the safety and efficacy of the device."
As to the shelf life of the matrix, the matrix is compressed "the matrix ... gradually re-expands Julia Carey-Corrado, MD, a medical officer at the Office of Device Evaluation, told the panel that the pivotal trial for the device was a single-arm study with a primary endpoint of the rate of pregnancy within a year after establishing reliance on the device.
"FDA was initially concerned that the trans-vaginal ultrasound might not be easily interpretable" in support of device placement. She said the agency was also concerned "how feasible it is to expect someone to hold that catheter stationary" because positional excursions could easily perforate tissues.
FDA's first question to the panel was whether safety data were clinically acceptable, with panel chair Marcelle Cedars, MD, the director of the Center for Reproductive Health at the University of California San Francisco, quickly summarizing that the panel "generally believes that the safety profile is favorable."
The second question was whether the study's effectiveness rates were clinically acceptable. The panelists indicated that efficacy may suffer when the device goes into general use. Despite minor reservations, panelists were comfortable with effectiveness rates overall.
One panelist noted that if the typical age of sterilization was the 30s, these devices will be in place for several decades. He said that the 10-year failure rate (pregnancy) for the Hulka Clip (made by Richard Wolf Medical Instruments, Vernon Hills, Illinois) was about 10 times that of the one-year rate of 3.7%, a cause for concern.
The panel voted unanimously to require a mandatory 10-year follow-up for the pivotal trial subjects. The condition to require recruitment of new physicians and patients to follow-up to an endpoint of pregnancy drew full support, with one abstention.
The panel also recommended a perforation study in animal models, which passed with one nay (and one abstention), and a requirement for a comparator group in the PAS, which drew 12 ayes, no nays and one abstention.
The overall vote to approve was 10-3, a smaller majority than seen in the votes for conditions for approvability.
Ellen Sheets, MD, the chief medical officer at Hologic, told Medical Device Daily: "we don't expect significant [market] penetration in the next two years," noting that Essure has only taken 10% of the market despite coming out five years ago.
However, Sheets said that the availability of the Adiana would "absolutely" broaden the appeal of permanent sterilization. "The more devices there are, the more doctors" will be able to recommend a procedure that will be appropriate for their patients. Sheets added that "the market [for sterilization devices] is wide enough for two."
Danica Marinac-Dabic, PhD, chief of FDA's Office of Surveillance and Biometrics, told MDD that device makers can expect to see a greater emphasis on the use of comparator populations for PAS. She said that comparator populations are a new point of emphasis "since the epidemiologists took over the PAS program."
She added: "It's hard to put study data into context" without comparators, and that while concurrent controls may be required in some instances, historical controls may also be an option.