Device Maker Slammed by Injured Patients at FDA Meeting

Copyright Dickinson FDA Webview at www.fdaweb.com. Republished by permission.

2/24/2015

Avedro Inc. CEO David Muller was verbally battered by several injured LASIK patients during public presentations 2/24 at a joint meeting of two FDA advisory committees as he led his company’s efforts to win an approval recommendation for a new drug/device combination to treat eye disorders progressive kerataconus and ectasia. Muller, the presenters charged, headed Summit Technology in the 1990s when it won a corrupt approval for the first LASIK-indicated excimer laser that permanently damaged their eyesight and “ruined” their lives.

Now he’s seeking approval for an “orphan”-designated NDA for riboflavin ophthalmic solutions with UVA irradiation by Avedro’s KXL System for use in corneal collagen cross linking for the treatment of the conditions underlying progressive keratoconus and corneal ectasia following refractive surgery. Despite its unapproved status in the U.S., the combination is already being promoted on Avedro’s Web site as an integrated enhancement of LASIK surgery outcomes, restoration of corneal strength, halting progression of keratoconus and ectasia, and slowing or eliminating the development of acute keratoconus.

Before they voted 10-4 with one abstention to recommend approval for the keratoconus indication and 6-4 with four abstentions for the ectasia following refractive surgery (LASIK) indication, the Dermatologic and Ophthalmic Drugs Advisory Committee and Ophthalmic Devices Panel of the Medical Devices Advisory Committee heard 14 public commenters give four-minute presentations. The first four urged approval, citing worldwide successful use of the new technology outside the U.S., and the suffering of an estimated 2 million keratoconus American victims who are without access to the therapy.

There were 1,268 corneal transplants performed in the U.S. in 2013, the Cornea Society’s David Glasser told the panel. “I couldn’t be happier if your votes today mean I will have performed my last corneal transplant,” he said.

But the remaining 10 public presenters, while frequently conceding the case for keratoconus victims in Avedro’s new technology, delivered a relentless stream of condemnations of the refractive surgery medical-industrial-FDA collaboration that they complained had ruined their lives, led to depression and suicide through an “epidemic” of dry eye, blurred vision, starbursts, haloes, night-driving difficulties and other vision problems.

The panel also heard a presentation, delivered in his absence, by former CDRH ophthalmic devices branch chief Morris Waxler, who led the team that approved the first Summit Technology LASIK device and has since recanted. Delivering for him, injured LASIK activist Paula Cofer slammed Muller’s role as Summit Technology CEO in introducing the first LASIK lasers through a corrupt FDA evaluation process. She alleged that he was responsible for “thousands, perhaps tens of thousands of LASIK patients who developed ectasia as a result of their trust” in the process. LASIK surgeons, she said, don’t report the ectasia cases they cause, and are complicit in an industry-wide cover-up. If FDA approves Avedro’s combination product, she predicted it will lead to off-label use of Avedro’s next enhancement, LasikExtra, already being promoted on its Web site and in the marketplace.

Then it came Matt Kotsovolos’ turn [speaking for Dean Kantis] to lambaste Muller for “ruining” his vision through “huge” (reportedly $1 million) contributions to the late Sen. Edward Kennedy’s 1994 re-election campaign “in exchange for political FDA access” that led to the Summit device’s approval in October 1995. Kotsovolos also read from what he said was a transcript of a presentation to a professional group by the Cleveland Clinic Foundation’s Cole Eye Institute eye surgeon Ronald R. Krueger, in which he admitted that LASIK-caused ectasia occurred much more frequently than the procedure’s FDA-accepted 1% total adverse event rate.

Muller, who has long bragged about the closeness of his FDA relationships, took to the podium several times during the panel discussions, but he did not respond to his critics. In one appearance he explained that deficiencies in the clinical data supporting the KXL System application, pointed out by many panel members, resulted from data prepared by an unnamed “small German company” that developed the technology and ran out of money before it could complete the studies and Avedro acquired them as-is.

Among the Avedro data deficiencies mentioned by panelists were the NDA’s lack of patient satisfaction surveys, which CDRH ophthalmic devices director Malvina Eydelman told the meeting FDA was “committed to,” and the complete lack of any data from studies done with the KXL device itself ─ instead the panelists were forced to accept Avedro’s contentions that this device was to all important extents, identical to a different device, the UVX which was used in all the studies.

Despite these and other deficiencies, the panel voted with barely muted misgivings for the primary indication, progressive keratoconus, and much more reluctantly for the second ─ and reputedly far more profitable ─ ectasia after LASIK indication.

Ex-FDAer Waxler to Oppose Avedro NDA at Advisory Cte.

By Jim Dickinson

02/18/2015

Former CDRH ophthalmic devices branch chief Morris Waxler will next week oppose an Avedro Inc. NDA seeking approval for riboflavin ophthalmic solutions with UVA irradiation for use in corneal collagen cross linking for the treatment of the conditions underlying progressive keratoconus or corneal ectasia following refractive surgery. The venue: the 2/24 joint meeting of the Dermatologic and Ophthalmic Drugs Advisory Committee and Ophthalmic Devices Panel of the Medical Devices Advisory Committee.

The basic issue in Waxler’s opposition is the failure of the applicant to demonstrate long-term product safety in a prior LASIK PMA application as Summit Technology in 1995, which Waxler approved as branch chief.

In a presentation to be delivered in his absence, Waxler says the NDA presents “at least two public health dilemmas” for the committees because the product masks “a high rate of LASIK-induced ectasia” when the true rate is unknown, and “how many legally blind people are acceptable to you for a few years of ’20-happy vision?'”

Waxler’s presentation says that FDA’s “collaboration with the refractive surgery industry has created a LASIK-induced epidemic of sick corneas…. The true rate of LASIK-induced ectasia will be buried forever if the panel recommends approval of FDA’s plans to approve products polymerizing sick corneas.”

Waxler, who unsuccessfully petitioned against his own approval of the LASIK indication for excimer lasers because of alleged data falsification he found later, says FDA leadership on LASIK products “has a long-standing collegial and professional bias towards ophthalmic professionals in the industry. They work out many issues in regular private meetings; I know because I led many of these meetings and know of many others.”

LASIK Activists Petition for Black Box Warning

Copyright Dickinson FDA Webview at www.fdaweb.com.
Republished by permission.
01/05/2015

Notwithstanding a recent FDA-NIH-U.S. Navy collaborative study that downplayed LASIK vision-altering surgery risks, three activists petitioned FDA commissioner Margaret Hamburg 12/24/2014 to add a black box warning to the labeling of lasers approved for the procedure. The petition alleges a “high incidence of induced visual symptoms (double vision/ghosting, starbursts, glare, and halos) and dry eyes” and asks the agency to send letters to professional organizations “to advise physicians of a black box warning on excimer lasers.”

The petition says the FDA-NIH-Navy study “demonstrated that three months after LASIK eye surgery, up to 45% of patients who had no visual symptoms before LASIK report [them] after LASIK, and up to 30% of patients who had no dry eye symptoms before LASIK report dry eyes after LASIK.” It cites a 2007 published review of data from 12 FDA clinical trials showing that six months after LASIK about 20% of patients reported that visual symptoms and dry eyes were worse than before surgery, much worse than before surgery, moderately severe after surgery, or severe after surgery.

“With millions of people having undergone laser eye surgery with such frequent problems,” the petitioners write, “it follows that there is an epidemic of visual symptoms/night vision problems and dry eyes caused by this unnecessary surgery. Unless the FDA immediately begins to provide adequately strong black box warnings about the risks and adverse effects of laser eye surgery, the epidemic will continue to grow. There have already been several reports of LASIK-related suicide and countless reports of suicidal ideation. A black-box Warning would help reduce the number of such negative outcomes and therefore falls well within the FDA’s mandate of protecting and promoting public health.”

FDA Dims LASIK Harms it Found in ‘Life Quality’ Study

Copyright Dickinson FDA Webview at www.fdaweb.com. Republished by permission.

October 20, 2014

In a long-awaited report on a collaborative study it conducted on the post-surgical quality of life of LASIK patients, FDA is downplaying the harms it found in up to 45% of 572 patients, adopting the industry-favored term “visual symptoms” vs. the agency’s former use of the terms “adverse reactions” or “adverse events.” Delivered by CDRH ophthalmic devices chief Malvina Eydelman at a LASIK-friendly forum staged by the American Academy of Ophthalmology (AAO) 10/17 in Chicago and posted on FDA’s Web site 10/20, FDA’s report said “some” patients in the study developed “problems” after surgery like “difficulty driving at night or in sunshine, [that] severely impacted a patient’s daily living, and included debilitating vision symptoms (seeing starbursts, glare, ghosting, or halos) and severe dry eye.” It says nothing about psychiatric problems, depression and suicide linked to adverse LASIK outcomes; its limited scope (three months post-surgery) and small subject base virtually assured it would not reach those associations.

FDA’s collaborators in the study were the National Eye Institute and the Department of Defense (especially the pro-LASIK Naval Medical Center in San Diego which encourages service personnel to undergo LASIK and performs most of the LASIK procedures that ensue). The overall study consisted of two underlying initial studies known as PROWL-1 and PROWL-2 (for Patient Reported Outcomes With LASIK), the former being among military personnel and the latter among patients of five commercial LASIK surgical facilities, one of which, the 20/20 Institute in Indianapolis, received an FDA warning letter during the course of PROWL-2 for failing to disclose LASIK risks and thereby misbranding the laser it used.

FDA’s report listed its main findings as follows:

  • Up to 45% of participants, who had no visual symptoms before surgery, reported at least one visual symptom at three months after surgery.
  • Participants who developed new visual symptoms after surgery, most often developed halos. Up to 35% of participants with no halos before LASIK had halos three months following surgery.
  • Up to 30% of participants with no symptoms of dry eyes before LASIK, reported dry eye symptoms at three months after their surgery. (This is consistent with previous studies.)
  • Less than 1% of study participants experienced “a lot of” difficulty with or inability to do usual activities without corrective lenses because of their visual symptoms (halos, glare, et al) after LASIK surgery.
  • Participants who were not satisfied with the LASIK surgery reported all types of visual symptoms the questionnaire measured (double vision/ghosting, starbursts, glare, and halos).

“The findings from this study will help to refine our current thoughts on the labeling for LASIK devices which will be incorporated into our patient labeling guidance,” the report says. “In addition, we will ensure our Web site reflects these findings to better inform consumers of the potential outcomes following LASIK.”

Commenting on Eydelman’s 10/17 AAO presentation, which closely tracked the report FDA subsequently posted to its Web site, LASIK-injured patient advocate Paula Cofer picked up on her admission that “dissatisfaction and disabling symptoms may occur in a significant number of patients.” In a Web posting on LASIK Newswire, Cofer quoted Eydelman as saying that further analyses should be done to explore “other associations” with [LASIK patient] dissatisfaction, and that additional longitudinal studies should be conducted to “explore the factors associated with and predictors of poor outcomes.”

“Remarkably,” Cofer comments, “six years and many tax-payer dollars later, Eydelman is suggesting ‘further analyses’ and additional studies. LASIK critics say Eydelman is a pawn of the LASIK industry and should be fired, and the FDA should take immediate action to protect the public by withdrawing its approval of LASIK. Although LASIK critics say they feel vindicated by the early reporting on the LASIK study, they doubt anything will change.”

LASIK Study Shows Significant Number of Problems

October 19, 2014
Preliminary results from FDA study of LASIK show significant number of patients experience problems.

Presenting preliminary results of the long-awaited LASIK Quality of Life Study during a keynote lecture at a meeting of the American Academy of Ophthalmology in Chicago on 10/17/2014, ophthalmologist Malvina B. Eydelman, MD, director of the FDA’s Division of Ophthalmic and ENT Devices, said that “dissatisfaction and disabling symptoms may occur in a significant number of patients”.

Plans for a study to consider how LASIK impacts patients’ quality of life were initially announced in 2008 around the time of a public meeting of the FDA’s ophthalmic devices advisory committee. The meeting was called in response to growing public criticism of the procedure and widespread reports of serious injuries. Testimony at the meeting from members of the public included reports of life-altering LASIK injuries and stories of LASIK-related suicides. Department of Defense LASIK surgeons and representatives of organized ophthalmology groups strongly defended the surgery.

Although LASIK critics were in favor of re-evaluating LASIK safety, many were incensed at the FDA’s plan to partner with organized ophthalmology groups for a prospective study, accusing the agency of placing the fox in charge of the hen house.

More than a year elapsed with no word on the proposed study. Then in October 2009, the FDA issued a press release announcing plans for a government-funded LASIK Quality of Life Study in collaboration with the National Eye Institute and the US Department of Defense. Mysteriously, military LASIK surgeons had replaced organized ophthalmology groups in the planned 2-part clinical study.

An article in the December, 2009 edition of the Journal of the American Medical Association (JAMA) reported that Steve Schallhorn, MD, Capt, US Navy (Retired) is “confident that once the quality-of-life issues are studied, LASIK will be shown to be even more safe and effective.” LASIK critics accused the agency of trading one embarrassing collaborator with conflicts of interest for another.

As a side note, in January 2011, former FDA branch chief for ophthalmic devices, Morris Waxler, PhD, petitioned the agency to withdraw FDA approval for all LASIK devices and issue a LASIK Public Health Advisory. Waxler had been conducting his own review of LASIK safety, and had concluded that the agency had made a mistake in granting the approval.

Five more years passed after the FDA’s 2009 update on the LASIK study. During the six year wait for the study results, the practice of LASIK continued status quo while LASIK injury reports stacked up at the agency. Currently, there are thousands of LASIK injuries on file with the FDA, although LASIK critics insist most injuries are never reported.

With the LASIK Quality of Life Study finally complete, LASIK critics wait for the manuscript to be published. Meanwhile, they point to data that were reported in Chicago to support their assertion that the procedure does not meet FDA safety requirements and therefore should not be performed.

  • Thirty percent of subjects with no symptoms of dry eyes before LASIK, reported dry eye symptoms at three months after their surgery.
  • Nearly half (45%) of subjects who had no visual symptoms prior to LASIK reported one or more visual symptoms 3 months after LASIK. These include halos at 35 percent, followed by starbursts at 28 percent, glare at 16 percent, and ghosting at 6 percent.
  • Visual symptoms were “very” or “extremely” bothersome in up to 4 percent of subjects.

LASIK critics assert that adverse outcomes are more common than the current study shows, as ‘real world’ outcomes are never as good as those reported in clinical trials. Visual symptoms, which are discounted by the FDA in evaluating LASIK safety, accounted for the majority of dissatisfaction with LASIK.

Ten percent of eyes did not achieve 20/20 vision, although subjects were presumably treated using the “latest technology.” Only 63.1% of subjects in study-1 and 53.5% of subjects in study-2 were “completely satisfied” with their vision at 3 months after LASIK.

The study included only 262 military subjects treated at the US Naval Medical Center San Diego with 6-month follow-up and 312 civilian subjects treated at five clinical sites across the US with 3-month follow-up. LASIK critics point to studies which suggest that LASIK results decline over time and published case reports of sight-threatening late onset complications which indicate that problems may present months or years after seemingly successful LASIK.

Moreover, average nearsightedness of subjects was just 2.5 diopters in study-1 and 3.6 diopters in study-2. Had the investigators included more patients with stronger prescriptions, the outcomes would have been even worse.

In her closing remarks, Eydelman is quoted as saying, “Further analyses are needed to explore other associations with dissatisfaction, and additional longitudinal studies are recommended to explore the factors associated with and predictors of poor outcomes.”

Remarkably, six years and many tax-payer dollars later, Eydelman is suggesting “further analyses” and additional studies. LASIK critics say Eydelman is a pawn of the LASIK industry and should be fired, and the FDA should take immediate action to protect the public by withdrawing its approval of LASIK. Although LASIK critics say they feel vindicated by the early reporting on the LASIK study, they doubt anything will change.
***
Sources for this article include:
(1) “FDA program tracks post-LASIK patient-reported outcomes.” Ocular Surgery News. Healio. Web. 17 Oct. 2014.
(2) Krader, Cheryl Guttman. “LASIK Quality of Life Collaboration Project characterizes benefit, burden.” Ophthalmology Times. Modern Medicine. Web. 17 Oct. 2014.
(3) Mike Mitka. “FDA Focuses on Quality-of-Life Issues for Patients Following LASIK Surgery.” JAMA.2009;302(22):2420-2422.
(4) Frederick Ferris, MD. PowerPoint presentation at AAO convention. 19 Oct. 2014.
(5) “LASIK Quality of Life Collaboration Project.” FDA. Web. 20 Oct. 2014.
(6) Larkin, Howard. “FDA Releases LASIK Patient Survey, Warns Of Large Numbers Of Dissatisfied Patients.” EuroTimes. Web. 20 Oct. 2014.
(7) Malvina Eydelman, MD. “LASIK Quality of Life Collaboration Project: Study Results Presented at the Refractive Surgery Subspecialty Day of the American Academy of Ophthalmology (AAO) on October 17, 2014” (PDF) FDA. Web. 21 Oct. 2014

Give FDA Authority over All Medical Device Ads?

Copyright Dickinson FDA Webview at www.fdaweb.com. Republished by permission.
8/2/2014

Historically, U.S. law has given the Federal Trade Commission (FTC) primary authority to regulate the advertising and other promotion of prescription medical devices not otherwise “restricted” by FDA.

Restriction most commonly occurs in the conditions of approval stipulated in writing by FDA at the time of PMA approval, leaving the overwhelming majority of Class I and II devices unrestricted and therefore subject only to FTC, and thus scant, regulation of their advertising and promotion.

This is in stark distinction to other FDA-regulated prescription medical products, primarily drugs and biologics, which are unequivocally regulated in their promotional activities by FDA.

In practice, this has meant that the advertising and promotion of prescription drugs and biologics have been much more closely regulated than the marketing claims commonly made for most medical devices.

Lacking the in-house scientific backup that FDA has, FTC’s interest in medical devices has been minimal, a neglect that many Washington device lawyers justify by citing a fundamental difference between devices and drugs: the former’s characteristic ongoing and frequent design and materials change throughout the product life cycle, versus the latter’s static adherence to the formula, ingredients and indications as approved by FDA.

Arguments that there should be a public safety-based regulatory consistency for both categories of medical products frequently get short shrift from legal scholars.

But consider the case of hyper-advertised LASIK excimer lasers, which are “unrestricted” Class III devices and are therefore in FTC’s regulatory bailiwick, where they enjoy an unrestricted advertising world of bright-eyed people who’ve thrown away their glasses forever after what the ads portray as a quick and easy, painless procedure with a high-tech laser.

If you listen to CDRH former CDRH Diagnostic and Surgical Devices branch chief Morris Waxler, who approved the LASIK devices and Harvard assistant clinical ophthalmology professor Perry Rosenthal, who has studied their effects, you’ll glimpse the dark underbelly of FDA and FTC regulatory negligence. Here there’s an alleged LASIK adverse event rate that’s 20 times higher than FDA accepted when it approved the LASIK indication, and industry-dependent professional ophthalmology journals that reject papers trying to draw attention to it.

LASIK (laser in-situ keratomileusis) is a popular in-office procedure in which a U-shaped flap is cut by microkeratome blade in the surface of the cornea over the iris, the underlying stroma is contoured with an excimer laser, and the flap then folded back in place. However, untold to patients, the flap never heals, and is always prone to dislodgement and infection in such violent activities as contact sports and accidental trauma.

Waxler, who led the review team that approved the first of these lasers for LASIK in the late 1990s, was content with the decision until 2004, when a volatile and outraged Florida microjet salesman, Dean Kantis, tracked him down, now retired in Madison, Wisconsin.

Kantis operates a flamboyant Web site and belongs to country-wide networks of other injured LASIK patients. All allege they had received no FDA-required patient informed consent, namely the agency’s approved product-specific patient information brochure. LASIK surgeons do not answer to FDA because medical practice is regulated at the state level.

Kantis connected Waxler to other injured patients around the country. At first the retired FDA veteran was wary, but he gradually became sufficiently intrigued to begin personally researching the stories of the severely injured LASIK patients (including the mother of patient she said committed suicide due his LASIK injuries) and re-analyzing the industry-submitted PMA data on which he had relied to approve the devices. After five years in this effort, Waxler petitioned FDA in 2011 to withdraw the devices’ LASIK indication and issue a public health advisory.

Waxler’s conclusion: to get PMA approval, the laser makers had submitted fraudulent data to FDA attesting to a less-than-one-percent incidence of post-LASIK adverse events. Waxler’s re-examination of the PMA data revealed an incidence of more than 20 percent.

On this basis, the other 80 percent have no post-surgery problems, thus explaining, in part, the paucity of public complaints. Also the same devices have therapeutic, non-LASIK uses that are uncontroversial.

Meanwhile, Harvard Medical School assistant clinical professor of ophthalmology Perry Rosenthal had come to a parallel conclusion about the hidden LASIK adverse events.

Rosenthal identified and studied 21 patients who developed “unrelenting agonizing” eye pain following LASIK surgery, pain that had persisted for 2-15 years at the time of the study. He found that their pain was so “devastating and resistant to treatments that most of these patients admitted to thoughts of suicide.”

Rosenthal also discovered that the onset of this “neuropathic” eye pain was delayed in the majority of these patients, sometimes for many years after their eyes had healed and were comfortable. This type of pain had not been reported in the medical literature and because these eyes typically looked normal the sufferers had been accused of exaggerating or fabricating their suicide-provoking pain.

Nevertheless, his paper detailing these findings was rejected by two peer-reviewed ophthalmology journals and Rosenthal says he was forced to post it on his nonprofit Web site to avoid it being buried. He estimates there are 800,000 LASIK procedures every year worldwide and the available pool of surgical candidates is growing by 2 million eyes per year.

Rosenthal’s next step was to send his paper to FDA, despite being warned that the agency would not respond. FDA not only blew off Rosenthal’s study, it also blew off Waxler’s petition, just as it had previously blown off Kantis’ angry and insulting tirades (“Go to FTC,” it told him, but he found that agency to be just as disinterested as FDA).

After a 30-month wait, this past June Waxler received FDA’s formal denial of a petition he had filed seeking removal of the LASIK indication from all excimer lasers.

On July 22, he plunged onward, filing a petition for reconsideration in which he charged that FDA “grossly underestimates the risks of LASIK by conflating data used to legally support the PMAs with LASIK industry information used to promote sales.”

In doing so, he wrote, CDRH had sent two messages: that the LASIK industry could feel secure because “the agency has your back,” and that the public should beware because “FDA does not have your back.”

Waxler told the agency that it had “made deals” with the LASIK industry that “degraded the scientific quality of the collection and analysis of adverse event data of LASIK devices.”

He listed alleged deals with the following entities: Kremer Laser, American Society for Cataract and Refractive Surgery, CRS Inc., and more than 100 user facilities that he says received IDEs “to study LASIK in order to minimize their exposure to violating off-label rules.”

Would giving CDRH the authority to regulate all medical device advertising change its subservience to industry?

The only model we have is the more tightly regulated market environment for prescription drugs and biologics at CDRH’s sister Center for Drug Evaluation and Research (CDER), where historically promotional activities have been strenuously regulated. CDRH has a staff of three to review restricted device promotional activity, while CDER boasts a staff of 60 for this kind of work.

Medical device lawyers and proponents abhor the prescription drug regulatory template for the industry’s products, and the 1976 Medical Device Amendments and subsequent legislation have been careful to avoid such an imposition.

But when it comes to marketing and advertising at least, the LASIK experience gives us pause.