FDA Webview (reprinted with permission)
5/15/2009

510(k) Route to Market Under New Attack

Two new pointers to the inadequacy of Sec. 510(k) to protect public health and safety emerged last week in a New York Times exposé of vaginal sling toxicity and new medical literature reporting elevated safety issues with new ophthalmic lasers. Both devices, substantially different from the “predicate” devices they referenced in their “substantially equivalent” 510(k) submissions to FDA, are now the subjects of liability or malpractice lawsuits. They add to a growing list of earlier examples of problems with 510(k) reviews in CDRH that cited other devices and are currently under Congressional scrutiny. One, ReGen Biologics’ Menaflex, is the focus of an internal FDA re-examination ordered by acting commissioner Joshua Sharfstein.

FDA’s current advice on what makes a device “substantially equivalent” relies on whether, “in comparison to a predicate, it:

• has the same intended use as the predicate; and
• has the same technological characteristics as the predicate;
  or
• has the same intended use as the predicate; and
• has different technological characteristics and the information submitted to FDA;
  • does not raise new questions of safety and effectiveness; and
  • demonstrates that the device is at least as safe and effective as the legally marketed device.”

In practice, a predicate can be a device that has been marketed for so short a period of time it has not established a meaningful safety record, and it can be a part of a string of such predicates.

The New York Times exposé cited adverse reactions leading to repeated surgeries for women using Mentor Corp.’s ObTape internally to control urinary leaks. The device was approved under a 510(k) that asserted it was “substantially equivalent” to older products, Johnson & Johnson’s Tension Free Vaginal Tape System and American Medical Systems’ Sparc Sling System which were themselves, in turn, 510(k)’d as “substantially equivalent” to J&J’s Protegen sling, recalled in 1999 and described by FDA then as “adulterated and misbranded.”

The newspaper recounted life-altering miseries characterized by persistent, painful and often bloody vaginal discharges, fear of cancer and a feeling that “I’m stuck with this for the rest of my life.”

According to the Times report, FDA declined requests for an interview and in an email answered that “Any legally marketed device can serve as a predicate for a premarket submission,” even if it has been recalled and called “adulterated and misbranded.” A subsequent 5/10 editorial said FDA “needs to take a hard look at whether it has been too lenient in clearing medical devices that may not be safe.”

In the ophthalmic lasers example, injured LASIK patients circulated on the Internet a Journal of Cataract & Refractive Surgery editorial by William J. Dupps, Jr. that commented on a University of Toronto clinical study of 149 eyes treated with a 15kHz Intralase femtosecond laser in which 56% were associated with an adverse event called opaque bubble layer (OBL). New-generation lasers with higher pulse frequencies may be less likely to cause OBL, Dupps said. All these devices entered the market through 510(k) clearances. Although OBL only rarely impacts visual acuity at three months post-procedure, it is part of a growing number of “a new array of complications” with femtosecond lasers, which are used to bladelessly create corneal flaps preparatory to LASIK reshaping. According to injured patients, these include corrugated corneal stromal bed, extreme light sensitivity, partial flaps, rainbow glare, torn flap, vertical gas breakthrough, epithelial ingrowth, flap necrosis, diffuse lamellar keratitis (DLK), corneal perforation, incomplete flap, decentered flaps, small flaps, slipped flaps, flap folds, traumatic flap dislocation, gas bubbles in the anterior chamber, optic nerve damage, flap tears, haze, macular hemorrhage, infection, stromal cell necrosis, inflammation, keratocyte cell death, corneal nerve damage, goblet cell reduction, and interface particles.

The Intralase devices were cleared on the basis of their “substantial equivalence” to a string of six other Intralase 510(k)’d predicates going back to 1999.

The study Dupps cited concluded that OBL was associated with thicker corneas and smaller corneal flaps and “did not seem to have detrimental long-term sequelae, although a small harmful effect could not be ruled out.”

Unlike the ObTape victims, the far more numerous injured LASIK patients support numerous Web sites and have formed networks in which they complain of permanent vision loss and a wide array of sight defects, inadequate or false advice from surgeons before undergoing the procedure, and FDA failure to investigate ambulatory surgical facilities for failure to report adverse events to FDA.

Responding to an FDA Webview request for comment on the vaginal sling and LASIK examples, FDA press officer Siobhan DeLancey said the majority of patients in both “report a positive outcome. However, we are aware that a small percentage of patients do experience serious adverse events. We released a Public Health Notification last fall about these surgical meshes used for stress urinary incontinence and pelvic organ prolapse (the indications mentioned in the NYT article), and that PHN can be found at http://www.fda.gov/cdrh/consumer/surgicalmesh-popsui.html. We are also in the process of a consumer education initiative on LASIK and held a public meeting last year to encourage the reporting of adverse outcomes. That information can be found at our advisory committee site (http://www.fda.gov/ohrms/dockets/ac/cdrh08.html#Ophthalmic, please see the information for the April 25, 2008 meeting).

“It’s important to note,” she continued, “that the report of an adverse event is not proof that a device caused the event. If the data reviewed by the FDA suggests a possible link between an adverse event and a device or use of a device, we may require further study before issuing a PHN or other health advisory.

“Adverse event data is not necessarily useful in making a direct correlation between a device and the event. The FDA uses this data to look for trends and safety signals of potential problems that most likely require further study and more intensive follow-up.”

On the LASIK issues, DeLancey said the agency had allowed a follow-up interview 5/14 by Consumer Reports with CDRH director of ophthalmic and ENT devices Malvina B. Eydelman. In that, Eydelman apparently provided a long list of FDA accomplishments since the 4/08 advisory committee meeting on patient injuries, including development of an FDA LASIK Web site; updating LASIK-related information in the SightNet program for health professionals to emphasize that halos, glare, night vision and dry eye problems from LASIK should be reported to FDA; developing a patient information card with the American Academy of Ophthalmology to help LASIK doctors calculate the lens implant power should they need to have future cataract surgery; recognizing the new LASIK standard from the American National Standards Institute; and opening a public docket for LASIK so that any interested person can pose comments, or concerns. This docket is web based and all comments submitted are able to be viewed by the public. All comments on the docket are examined and assessed by FDA staff on a regular basis.

“We are also working on collaborative agreements with organizations that have expertise in evaluating quality of life after LASIK,” DeLancey said. “We are currently collaborating with the National Eye Institute (NEI) on a pilot study to validate the web-based administration of previously validated paper versions of ophthalmic health-related questionnaires. Web-based administration of such questionnaires will help facilitate the pivotal study of patient-reported outcomes after LASIK.

“The pilot study is the first of its kind in the area of ophthalmology. Subjects with ocular surface disease and subjects with a normal ocular surface are being enrolled. People interested in participating in the pilot study at the NEI of the National Institutes of Health (NIH) in Bethesda, MD, and getting a free screening for dry eye and other ocular surface diseases, can learn more about the study by going to http://clinicaltrials.gov/ct2/show/NCT00678860?term=NCT00678860&rank=1.”