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CDRH Practices Finally Get Attention in 510(k) Probe


It has taken at least 15 years, but in May, the systemic “corruption” in CDRH's management processes finally got serious attention. Deputy commissioner Joshua Sharfstein ordered an internal, high-level reexamination of the way ReGen Biologics's Menaflex collagen scaffold received its entry to market.
This inquiry occurred as the public list of other 510(k) clearances that should have gone through the premarket approval (PMA) process began to expand. The list includes Mentor Corp.'s ObTape vaginal sling for urine leaks and Intralase's femtosecond laser for bladelessly creating corneal flaps for LASIK vision improvement surgeries.
ReGen Biologics consulted with its home state (New Jersey) congressional delegation to ensure a “fair” 510(k) review at CDRH after review scientists insisted that the device needed a PMA, not a 510(k) submission. The politicians contacted FDA as requested. CDRH director Daniel Schultz then overrode seven dissenting subordinates and gave Menaflex 510(k) clearance last December.
The First Amendment guarantees all of us (including companies such as ReGen) the right to petition the government for a redress of grievances, and ReGen certainly felt it had a grievance with those reviewers at CDRH.
Sharfstein will lead a task force to focus on improving transparency of FDA’s product-approval decisions.
But there are ways and then there are other ways. Sharfstein's internal review of what happened will properly focus on the Menaflex review in isolation. But after that, the new public health team heading FDA will have a perfect opportunity to delve into the process corruption that is both peculiar to CDRH and something to which I have tried to draw attention for 15 years.
It is also something for which I have been shunned by a succession of CDRH directors—starting with Bruce Burlington in 1995. I highlighted corrupt review and compliance procedures exerted against the small maker of dental muscle monitors, Myo-Tronics. Of course, the word “corruption” is too often equated with “bribery,” which was Burlington's main complaint.
But all center directors since Burlington, including Schultz, have been unwilling to forage in the organizational mud below them to cleanse it of bad actors, bad procedures, and bad results brought to their attention by complaining companies (think Myo-Tronics, Utah Medical Products, TMJ Implants) and citizens. To look into these issues would be tough, adversarial, and resource-consuming work, when directors and even commissioners would understandably much rather promote and communicate their organization's accomplishments and program needs.
As one prominent food and drug lawyer puts it, CDRH directors and FDA commissioners have tended to be more ambassadors than troubleshooting repairmen.
This may change in the opening era of Margaret Hamburg as commissioner and Sharfstein as her principal deputy. Both are possessors of impressive public health qualifications and track records—the first such team FDA has had at its helm.
As Alliance for a Stronger FDA leader Steven A. Grossman puts it, “public health is about helping people and communities to get healthy and stay healthy. Prevention is preferred because it preserves health, while therapies ‘only' restore health. Preferring prevention is not the same as being against therapy. Public health is not antitherapeutic nor could any FDA commissioner be antitherapeutic.”
Industry, as well as FDA reviewers and their managers, may have a hard time adjusting to this mind-set after so many years of living with corrupt processes. But, as Grossman says, ultimately it will be good for FDA and for all of us. A new and stronger FDA scheme is likely to come, starting with a reexamination of the Menaflex 510(k) and then on to fixing the deeply flawed 510(k) clearance process more broadly. Such efforts will likely require congressional intervention and legislative remedies.
As a persistent group of nine CDRH dissident scientists and physicians wrote to the Obama transition team and Congress in January, FDA also requires renovation of the organizational structure of the various centers and offices to restore internal checks and balances that proactively prevent corruption and manipulation of facts, science, and data. At present, FDA is plagued by a heavy-layered top-down organizational structure that concentrates far too much power in isolated offices run by entrenched managers where cronyism is paramount. We recommend that the Office of Device Evaluation be dismantled and split into multiple offices, each headed by a physician or scientist with strong leadership credentials and extensive clinical and technical expertise in the specific devices they regulate. These leadership positions should be rotated on a regular basis.
The ObTape and femtosecond LASIK examples support the case well. The examples came in a well-researched and well-written New York Times exposé of ObTape's toxicity and in new medical literature reporting elevated safety issues with new ophthalmic lasers.
Determining Substantial Equivalence

FDA's current advice on what makes a device "substantially equivalent" is displayed on CDRH's Web site. The answer relies on whether, in comparison with a predicate, the medical device in question

• Has the same intended use as the predicate and
• Has the same technological characteristics as the predicate.
• 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, FDA's equivalence stance means that a predicate can be a technologically different device that has been marketed for so short a period of time that it has not established a meaningful safety record. It can also be a part of a string of such predicates.
Both devices, which are substantially different from the predicate devices the manufacturers referenced in their 510(k) submissions to CDRH, are now the subjects of liability or malpractice lawsuits. (See the sidebar, “Determining Substantial Equivalence.”) They add to a growing list of problems with 510(k) reviews in CDRH that cited other devices, as well as parallel issues in PMA reviews that are currently under congressional scrutiny.
The New York Times piece cited adverse reactions leading to repeated surgeries for women using ObTape internally to control urinary leaks. The device was approved under a 510(k) that asserted it was substantially equivalent to older and technologically different products: Johnson & Johnson's Gynecare TVT (tension-free vaginal tape) and American Medical Systems' Sparc Sling system. These two devices, in turn, received 510(k) clearance as substantially equivalent to J&J's Protegen sling. The Protegen was 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 responded via e-mail that “any legally marketed device can serve as a predicate for a premarket submission,” even if it has been recalled and described by the agency as “adulterated and misbranded.” A subsequent Times editorial called on the agency 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 a Journal of Cataract & Refractive Surgery editorial by William J. Dupps Jr. on the Internet last year. It commented on a University of Toronto clinical study of 149 eyes treated with a 15-kHz Intralase femtosecond laser. About 56% of the cases dealt 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.
LASIK Complications

According to the injured patients, the new array of complications from LASIK surgery includes corrugated corneal stromal bed, extreme light sensitivity, partial flaps, rainbow glare, torn flap, vertical gas breakthrough, epithelial ingrowth, flap necrosis, and corneal perforation. Other conditions such as optic nerve damage, incomplete flaps, decentered flaps, small flaps, slipped flaps, flap folds, traumatic flap dislocation, and gas bubbles in the anterior chamber have also been reported.
Although OBL only rarely affects visual acuity at three months postprocedure, it is part of a growing number of what Dupps called “a new array of complications” with femtosecond lasers, which are used to bladelessly create corneal flaps for LASIK reshaping. (See the sidebar, “LASIK Complications,”)
The Intralase devices were cleared on the basis of their substantial equivalence to a string of six other Intralase predicates that received 510(k) clearance dating back to 1999.
The fluctuating—and in many cases suppressed—universe of complications and adverse patient experiences with rapidly advancing medical technology will challenge the new FDA leadership's commitment to promoting public health through prevention. Whether this means impeding the 510(k) rush to market while safety issues are more deeply assessed remains to be seen.
Unlike the ObTape victims, the far more numerous injured LASIK patients currently contribute to a ring of Web sites and have formed networks in which they discuss LASIK-related problems. Such problems include permanent vision impairment and an array of sight defects, inadequate or false advice from surgeons before undergoing the procedure, and FDA's failure to investigate ambulatory surgical facilities for not reporting adverse events to the agency.
Responding to my request for comment on the vaginal sling and LASIK examples, FDA press officer Siobhan DeLancey said that the majority of patients in both cases 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 [PHN] last fall about these surgical meshes used for stress urinary incontinence and pelvic organ prolapse (the indications mentioned in the Times article), and that PHN can be found at 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 (; please see the information for the April 25, 2008, meeting).
DeLancey emphasized “that the report of an adverse event is not proof that a device caused the event,” and that FDA may require further study before issuing a notice if the data reviewed by the agency suggest a possible link between an adverse event and a particular device.
“Adverse event data [are] not necessarily useful in making a direct correlation between a device and the event,” she said. Rather, the agency uses the data to spot “trends and safety signals of potential problems that most likely require further study and more-intensive follow-up.”
On the LASIK issues, DeLancey said that the agency had allowed a follow-up interview on May 14 by Consumer Reports with CDRH director of ophthalmic and ENT devices Malvina B. Eydelman. In that interview, Eydelman apparently provided a long list of FDA accomplishments since last year's advisory committee meeting on patient experiences, including
• The development of an FDA LASIK Web site.
• An update of 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.
• The development of a patient information card with the American Academy of Ophthalmology to help LASIK doctors calculate the lens implant power, should the patient need to have future cataract surgery.
• Recognition of the new LASIK standard from the American National Standards Institute.
• The opening of a public docket for LASIK so that any interested person can submit comments or concerns. (This docket is Web based and all submitted comments can be viewed by the public. The comments on the docket are examined and assessed by FDA staff on a regular basis.)
DeLancey said the agency is also collaborating with “organizations that have expertise in evaluating quality of life after LASIK,” including the National Eye Institute (NEI). FDA is working with the group on a pilot study to validate the Web-based administration of previously validated paper versions of ophthalmic health-related questionnaires. Such questionnaires “will help facilitate the pivotal study of patient-reported outcomes after LASIK.”
The pilot study, which is currently enrolling participants with ocular surface disease and those with a normal ocular surface, is the first of its kind in ophthalmology. DeLancey said that “people interested in participating in the pilot study at the NEI of the National Institutes of Health in Bethesda, MD, and getting a free screening for dry eye and other ocular surface diseases can learn more about the study” by visiting the following URL:
Copyright ©2009 Medical Device & Diagnostic Industry
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