Saturday, July 10, 2004

From Friday's Wall Street Journal: After Medtronic Lobbying Push,The FDA Had Change of Heart($$)
In May, an article posted on a prominent medical journal's Web site raised concerns about the long-term safety record of a device to treat bulges in the main artery leading from the heart. Now, all that remains on the site is the title.

The article, written by Food and Drug Administration researchers, focused on the AneuRx stent graft, a 5-inch metal-and-fabric cylinder designed to prevent deadly ruptures of the arterial bulges, called aneurysms. It suggested that, over time, a rival treatment -- invasive surgery -- was safer.

The device's maker, Medtronic Inc. of Minneapolis, sharply disputed the study's conclusion, reprising arguments from 2003 when it quietly persuaded the FDA to tone down a public notice on AneuRx's safety. Medtronic objected to the FDA that the authors used confidential data without permission. Its lawyer also threatened the editors of the Journal of Vascular Surgery with "criminal and civil sanctions" if they didn't pull the article from the Web site. In the end, the FDA asked the journal to remove the paper from the site, and in late June the agency officially withdrew it from publication.

The story of Medtronic's vigorous lobbying behind closed doors to modify the conclusions of midlevel FDA specialists offers a rare look at the agency handling a complaint by a big company.

The episode also shines a spotlight on a topic of intense debate: What right does the public have to see the information companies collect about their drugs and medical devices? Today, companies reveal important data to the FDA, but the agency typically releases only the information that it thinks is essential for doctors to know. The idea is to avoid confusion or overreactions and protect companies' proprietary data, which the FDA is generally prohibited from disclosing. Now some critics are calling the system inadequate, citing the example of industry findings about possible dangers of antidepressants to children that weren't published.
This has drawn the ire of the study's authors, Dr. Dale Tarvis and Dr. Lazar Greenfield (yes, that Greenfield). Aortic stent-grafting has become big business with Medtronic selling 10,000 AneuRx devices a year to the tune of $200 million. Aortic stent-grafting has fallen victim to the "man with a hammer" trap of medical devices. When the devices were first used their indications were for patients that had severe medical contraindications to conventional aneurysectomy. The importance of this distinction will become clear later. Gradually the indications widened to include those patients with "hostile abdomens" and now to where if a patient has an aneurysm and meets the anatomic guidelines they are offered the procedure. Patients also have begun to demand the procedure.
In April 2001, two years after AneuRx was approved, the FDA put out a health notice warning of possible problems with the AneuRx and a competing device. One concern was "migration," meaning that the AneuRx might move from the spot where it was implanted. The notice also cited possible leaks in which blood flows outside the device into the aneurysm, thus leaving a continued risk of rupture.

The notice didn't answer a crucial question: Do these problems make the AneuRx riskier overall than surgery?

The FDA turned to that question in 2002, preparing a public notice to doctors. Studies and interviews with vascular surgeons indicate that at top hospitals, the short-term mortality rate for surgery is very low. Typically, about 1% to 2% of patients die in such hospitals after the operations. At two highly regarded programs, the University of Michigan and the Cleveland Clinic, the death rate is about 1%. But at community hospitals, the rate is thought to be in the 4% to 6% range.

In an internal 2002 draft of its notice to doctors, FDA officials cited the lower 1% to 2% figure as the most suitable comparison for the AneuRx data being supplied by Medtronic. The hospitals that treated the AneuRx patients included in Medtronic's data were the same type of high-volume hospitals that had good results in surgery, so the authors of the draft considered this an apples-to-apples comparison.

AneuRx fared badly in the face-off. Its aneurysm-related mortality rate in the initial period after implantation surgery -- the period when surgical complications usually arise -- was around 1.5%. That was no better than the open-surgery rate cited in the draft. And the draft said long-term mortality from aneurysm-related causes was worse for the AneuRx than for open surgery.

The FDA draft concluded by recommending that AneuRx not be used when a patient's chance of dying during or shortly after surgery was less than 2%. That would effectively rule out the device for some patients.
That is, the device should only be used in patients with severe medical co-morbidities. The April 2001 warning is here. An excerpt:
AneuRx® System (Medtronic AVE)

This device has a fabric graft supported along its entire length by a series of metal rings sutured to the graft. The endograft is held in place by the radial force applied by the rings to the patient’s aorta. FDA is concerned about reports of approximately 25 aneurysm ruptures, as well as other serious adverse events, in patients who have received AneuRx®. Factors thought to be associated with the adverse events, including aneurysm ruptures, include: sub-optimal placement of the graft; endoleak (inadequate proximal seal, collateral vessel retrograde flow, persistent perigraft flow); migration of the main body of the device as well as any attachment cuffs, possibly associated with continuing aortic dilatation; problems with device integrity, due to metal frame fractures, suture breaks, or fabric tears; and aneurysm anatomy. We are working with Medtronic AVE to obtain relevant data that will help us understand how these problems affect the overall risk/benefit assessment of this product.
So Medtronic then brings its guns to bear on the FDA parading experts that attacked the methodology of the trials. The FDA then modified their recommendations and they may be found here. Back to the WSJ
The tug of war seemed to have been resolved. Then on May 7 of this year, an article called "Aneurysm-related mortality rates in the US AneuRx clinical trial" appeared in the Journal of Vascular Surgery's online preview section. Its authors were Dr. Tavris and two FDA colleagues, as well as Dr. Greenfield, the University of Michigan vascular-surgery professor.....

The paper relied on the same Medtronic data used by the FDA in preparing its public-health notice. The paper revived the 1% to 2% open-surgery death rate, saying a low figure was most relevant for comparison because the AneuRx recipients covered in the data were at institutions that treated lots of aneurysms.

The paper concluded that the mortality rate for patients getting the AneuRx probably exceeded that for surgical patients by three years or more after the treatment, because the AneuRx had little advantage in preventing immediate post-surgical deaths and caused or allowed more problems down the road.

Medtronic responded in a letter to the FDA dated May 20, asserting that the paper's authors were using confidential company data without permission. The letter argued again that the article was underestimating the surgery death rates. Medtronic said it had reached agreement with the FDA about the December public-health notice and the article went "well beyond" the notice, "in some cases reverting to the position[s] in the initial draft ... which we ... believed were wrong and which were ultimately eliminated in the final version" of the notice.
So the lawyers got involved and fired off a letter to the Journal of Vascular Surgery demanding that the article be removed due to "disclosure of ... proprietary information and breach of confidentiality protections are subject to both criminal and civil sanctions which will be pursued vigorously if this situation is not remedied." The article was pulled and there is some finger-pointing between the authors, the editors of the JVS and the FDA about who gave the go-ahead to pull the article.
Shenanigans with aortic stent-grafts are not new, as the information about another once-popular system was described in the April 2001 memorandum:
Ancure® system (Guidant)

This device has a flexible, unsupported fabric graft prosthesis that is actively fixed in place on the ends by wire hooks that penetrate the vascular tissue. On 3/16/01, Guidant suspended production and announced a recall of all existing inventory. The company reported to the FDA that they had failed to report many device malfunctions and adverse events, including severe vessel damage associated with problems with the deployment of the device. There were also manufacturing changes that were not properly reported to the FDA. The manufacturer told FDA that an internal audit revealed problems with their complaint handling system, manufacturing quality systems, documentation procedures and training. The FDA is reviewing the firm’s Corrective Action Plan that addresses these problems. Once we receive evidence that the firm has appropriately changed their systems and procedures, and the FDA has reviewed their regulatory submissions, we will assess whether the product can be returned to the market.
(emphasis mine) That is why when you Google Ancure you get the first two-and-a-half pages are sites for law firms involved in suits. This in addition to a guilty plea and a fine of $92 million.
Ironically these companies got to great lengths to insure the competence of the physicians inserting the devices. Before being allowed to place the devices a physician had to attend didactic courses as well as deployment of the endografts in animals and models. When you began to place them in patients you were required to submit your workup (CT and angiograms) to the manufacturer. A representative then was present for your first five insertions. Only then were you allowed to keep grafts "on site". It seems to me that if the company went through so much trouble to keep the device out of the hands of stumblebums, they would be diligent about other aspects of manufacture. Guess not.
The device used by my group now is the Gore Excluder graft. So far they seem to have a good safety record.
If you believe it.
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