Medtronic Documents Spur New Questions

BY JOHN CARREYROU

A report by the Senate Finance Committee based on thousands of documents it subpoenaed from Medtronic Inc. raises new questions about the integrity of the medical research underpinning one of the medical-device maker's products.

Medtronic was "heavily involved in drafting, editing and shaping the content of medical journal articles" about the product—a bone-growth protein used in spine surgery called Infuse—even as it was paying the physicians who wrote those articles a total of $210 million for unrelated work, the Senate report alleges.

In one instance, a Medtronic employee recommended to one of the physicians not publishing a list of side ...

via online.wsj.com

...effects associated with Infuse in a 2005 journal article, company emails show. Medtronic marketing officials also urged inserting language into other journal articles touting the use of Infuse as better for patients than using bone harvested from their pelvises because of the pain associated with the latter, other company documents show.

Medtronic's influence extended to preparing a physician's 2002 speech to a panel advising the Food and Drug Administration on whether to approve the drug, the report alleges. The physician's disclosure to the panel at the time suggested his testimony was independent, but the company had in fact helped him draft it and paid him as a consultant the previous year, company documents show. Medtronic later hired the physician as an executive.

In response to the Senate report, Medtronic issued a statement saying it "vigorously" disagreed with any suggestion that "it improperly influenced or authored any of the peer-reviewed published manuscripts." The company also denied that it "intended to under-report adverse events" associated with Infuse.

Infuse, which is used to spur the fusion of vertebrae to reduce back pain, once brought up to $800 million in annual sales for Medtronic. But the drug has been a source of controversy for the company since 2008, when reports began surfacing of patient deaths linked to its use in the neck.

The FDA approved Infuse in 2002 only for use in one particular type of surgery involving the lower spine. But it became widely used in other types of surgeries, including neck procedures, after a series of medical-journal articles depicted those other uses as safe and effective. Doctors are free to use drugs beyond their official uses, but companies can't promote such "off-label" uses.

Those journal articles have since come under a cloud. Last year, Eugene Carragee, a professor of orthopedic surgery at Stanford University School of Medicine, published a study showing that 13 of the articles failed to report serious complications associated with Infuse and a sister drug called Amplify that hasn't been approved by the FDA. Dr. Carragee's study prompted the Senate inquiry that led to Thursday's report.

Although it was known that Medtronic had financial relationships with some of the physicians who wrote journal articles, the scale of the payments and how far back they went in time had not been fully disclosed until now.

Medtronic says the payments weren't connected to the journal articles. Rather, it said, "the vast majority" were "royalty payments made to compensate physicians for their intellectual property rights and contributions" to other company products.

The documents obtained by the Senate committee show that Medtronic paid four of the article authors—Scott D. Boden, Regis W. Haid, Volker Sonntag and Thomas A. Zdeblick—between $22 million and $34 million each from 1996 to 2010. Medtronic also paid a limited liability company connected to two other authors, John R. Dimar and Steven D. Glassman, nearly $65 million over the same period.

All six are spine surgeons with current or former university affiliations. Drs. Boden and Haid are based in Atlanta, Dr. Sonntag in Phoenix, Dr. Zdeblick in Madison, Wis., and Drs. Dimar and Glassman in Louisville, Ky.

Another 27 physicians who shared authorship of the medical journal articles received payments from Medtronic ranging from a few hundred dollars to $6.4 million over the same 15-year span, the Medtronic documents show.

Dr. Sonntag didn't respond to attempts to reach him for comment.

Dr. Zdeblick said he was "a minor author" on two of the Infuse articles and "saw those manuscripts only in their later stages and have no knowledge of their early preparation." He said the $34 million he received from Medtronic was "related to the spinal implants I have designed and hold 22 patents on." He added that he received no royalties for Infuse itself. However, some of his royalties were for a device that Infuse is encased in when it's inserted in the spine.

Dr. Haid said the $25.5 million he was paid by Medtronic was for patented contributions he made to a variety of Medtronic products, though not Infuse. He said the money didn't influence his judgment with regard to the two journal articles he participated in. "I hold myself to high standards of integrity," he added.

Dr. Boden said he wrote two early articles about Infuse without input from "any Medtronic personnel." He acknowledged receiving consulting payments from the company at the time, but said he disclosed them to his university and took "steps to manage potential conflicts." He added that most of the $28.8 million he received from Medtronic came later and was related to "intellectual property for future biologic products." However, Dr. Boden was also a co-author on a 2007 article about Amplify, by which time he had begun receiving large royalty payments from Medtronic.

Drs. Glassman and Dimar said their journal articles "were edited and published by ourselves" and added that they have reported Infuse's adverse effects "in numerous peer-reviewed publications." They said the money their limited-liability company received from Medtronic was royalties shared with three other surgeons.

In most of the medical journal articles, the authors didn't disclose their extensive financial relationships with Medtronic.

For instance, in the 2007 Amplify article, which was co-authored by Drs. Boden, Glassman and Dimar, the disclosure read in part: "No benefits in any form have been or will be received from a commercial party related directly or indirectly to the subject of this manuscript."

That year, Drs. Dimar and Glassman's limited liability company received $9.7 million in royalties for a system of rods, hooks and screws they used in conjunction with Amplify in the study, Medtronic documents show. The study also failed to report a probable link between Amplify and cancer that ultimately led the FDA to decline to approve the drug.

Medtronic's role in shaping the medical journal articles was similarly not disclosed. In June 2004, a Medtronic marketing executive recommended to a surgeon author not listing all the adverse events associated with Infuse in the manuscript of one article. That article was published the following year in the Journal of Bone and Joint Surgery without a table detailing the adverse events.

Dr. Carragee says the omission had serious health implications because the adverse events included instances of inflammation, neurologic problems and bone weakening that could have been forerunners of the problems some patients would later die from when Infuse was used off label in their necks.

In another example of Medtronic's role in molding what was supposed to be independent medical research, another of the company's marketing executives encouraged the authors of two medical journal articles to emphasize the pain experienced by a control group of patients who received pelvic-bone grafts instead of Infuse. A "bigger deal should be made of elimination of donor site pain with Infuse," the executive wrote in a 2001 email to one of the surgeon authors. "I would put that front and center in results, discussion and conclusion so that 'equivalent' results aren't received as a letdown."

In some instances, Medtronic employees drafted responses for the authors to concerns expressed by peer reviewers before publication, the company documents show.

In January 2002, Hallett H. Mathews, a spine surgeon based in Richmond, Va., appeared before an FDA committee tasked with advising the agency about whether to allow Infuse onto the market. Before giving his testimony, which was favorable to Infuse, Dr. Hallett told the committee: "I have no direct financial interest in the product under review here today and am not being paid for my participation in this meeting."

Though technically correct, the disclaimer didn't disclose that Dr. Mathews had been paid consulting fees by Medtronic in 2001 and that Medtronic had worked with the public-relations firm Ketchum to prepare his testimony to the committee that day. Dr. Mathews later went to work for Medtronic as an executive. He left the company last year. Dr. Mathews didn't respond to an attempt to reach him.

In an attempt to address concerns about the science behind Infuse, Medtronic has given a $2.5 million grant to Yale University to oversee two independent reviews of all of its clinical data on the drug. The company expects those reviews to be completed sometime next year.

Write to John Carreyrou at john.carreyrou@wsj.com

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Medtronic Helped Write, Edit Positive 'Infuse' Spine Studies - By John Fauber, Reporter, Milwaukee Journal Sentinel/MedPage Today

via medpagetoday.com

Highly positive studies published in peer-reviewed medical journals depicted Medtronic's spine fusion product as a major breakthrough in back surgery, but those studies were drafted and edited with direct input from company employees, while the doctors listed as authors were paid millions, according to a U.S. Senate investigation.

The company's heavy, undisclosed manipulation of information about its bone morphogenetic protein-2 product called Infuse included removing and downplaying concerns about serious complications linked to the product and overstating its benefits.

The Money Trail

Over the course of 15 years, Medtronic paid $210 million to a group of 13 doctors who co-authored the series of now-repudiated papers about the product. The payments also included two corporate entities associated with some of the doctors.

The investigation by Senate Committee on Finance was prompted in part by Journal Sentinel/MedPage Today investigations that showed how the practice of medicine has been corrupted by conflicts of interest involving doctors, drug and device companies, and medical journals.

The Senate report, to be released Thursday, details how Medtronic employees, including some working in the company's marketing department, covertly collaborated with the academic physician authors in producing 11 different papers between 2002 and 2009.

Such "ghostwriting," though not illegal, has been condemned as a breach of integrity and transparency because doctors and patients rely on information in those articles to make medical decisions, not knowing that the papers may contain biased, inaccurate, or potentially harmful information.

The Senate's findings highlight problems that should have been reported at least a decade ago, said Ray Baker, MD, a Kirkland, Wash., pain specialist who served on an advisory panel to Medicare and Medicaid on Infuse.

"I am just sad this happened," he said. "At every level when we thought, 'that wouldn't happen,' it happened. The integrity of our scientific literature is our foundation. It's what predicates our treatments."

Medtronic Denies

Medtronic disputed many of the findings in the Senate's report.

"Medtronic vigorously disagrees with any suggestion that the company improperly influenced or authored any of the peer-reviewed published manuscripts discussed in the report, or that Medtronic intended to under-report adverse events," a statement emailed by the company said.

The company said it reported the adverse events to the Food and Drug Administration and those risks also are listed the product label for Infuse. Medtronic also called the report's characterization of the payments to the doctors misleading and unfair.

"The vast majority of such payments were royalty payments made to compensate physicians for their intellectual property rights and contributions, not consulting payments," the company said.

In 2011, after the Spine Journal devoted an entire issue to repudiating Infuse research, the company, under its new CEO, Omar Ishrak, hired Yale University to oversee an independent review of the safety and effectiveness of Infuse.

"This sounds eerily familiar to many of the transgressions we've read about from the pharmaceutical industry," said Harlan Krumholz, MD, a professor of medicine at Yale University, when told of the Senate report. "It paints a picture of a company very heavily involved in the science; marketing contaminating the science; and the medical profession and researchers being complicit."

The Public Trust

"It's no wonder the public has lost confidence in the drug and device industries."

Krumholz is overseeing Yale's review of Infuse. Those results are expected in January.

Medtronic's behavior also drew sharp criticism from two key senators on the committee.

"Medtronic's actions violate the trust patients have in their medical care," Sen. Max Baucus, (D-Mont.), chairman of the committee, said in a statement. "Patients everywhere will be better served by a more open, honest system without this kind of collusion."

Senior member Chuck Grassley (R-Iowa) said the findings support the Physician Payments Sunshine Act that he and Sen. Herb Kohl (D-Wis.) authored. That legislation will require drug and device companies to disclose such payments beginning next year.

"The findings also should prompt medical journals to take a very proactive approach...," Grassley said in a statement. "...The public will benefit from more transparency and accountability on their part."

In response to the Senate investigation, Medtronic turned over more than 5,000 documents, including emails involving the doctors and Medtronic employees as well as 14 years of payments from Medtronic to the doctors.

The Infuse Story

In January 2002, Hal Mathews, MD, spoke glowingly about Infuse to a FDA advisory panel that was considering whether to recommend approval of the product.

Mathews, then a Richmond, Va., spine surgeon who had taken part in the pivotal Infuse clinical trial, told the panel he had no direct financial interest in the product and that he was not being paid to appear at the meeting.

However, a 2001 email shows that Medtronic worked with the New York-based public relations firm, Ketchum, to prepare Mathews' speech to the panel, which went on to recommend approval of the product.

In addition, though Medtronic told the committee that Mathews was not paid for any activity undertaken in January 2002, Mathews was paid under consulting arrangements with the company in 2001.

In 2007, Mathews was hired by Medtronic as its vice president of medical and clinical affairs.

From the Pen of Medtronic

An email indicated that a Medtronic marketing employee, Julie Bearcroft, was involved in editing a 2005 Journal of Bone and Joint Surgery article and recommended against publishing a complete list of complications related to the structural integrity of the fused area.

Those complications -- known as implant migration, subsidence, and end-plate fracture -- had been observed in a clinical trial and had been formatted in a detailed table, according to an internal Medtronic email. But, following the advice of Bearcroft, that table was not included in the published paper.

"I personally think it is appropriate to simply report the adverse events were equivalent in the two groups without the detail," Bearcroft wrote in a note on a draft of the article.

After the editing change was made, the lead author of the paper, Ken Burkus, MD, a Columbus, Ga. surgeon, sent a draft of the paper to his co-authors with the note, "this manuscript documents the superiority in clinical and radiographic outcomes with (Infuse)..."

Burkus, who got $6.4 million from Medtronic between 1998 through 2010, did not respond to an email seeking his comment.

Medtronic officials inserted into papers language that attempted to portray Infuse as a better, less painful alternative to the standard technique of using a small amount of a patient's own hip bone for fusing vertebrae, a claim that has been questioned by independent spine surgeons.

Giving Infuse the Edge

In 2001 and 2002, after viewing early drafts of a 2002 Infuse paper, Neil Beals, a Medtronic marketing official, recommended that the physician authors make "a bigger deal" out of the supposed pain reduction with Infuse.

Subsequently, a sentence was inserted in the paper stating that Infuse spared patients from being exposed to problems associated with using their own bone for the fusion.

In its review of Infuse last year, doctors writing in the Spine Journal said the often-cited donor site pain was less frequent and serious than Infuse proponents suggested.

In addition, in a draft of a 2003 paper the authors said that any pain at the site of the hipbone graft site had been resolved in the study subjects within a year of the surgery. But Beals questioned that and inserted language saying residual effects of the donor site should be noted.

The final article appears to have adopted his suggestions, noting that even 24 months after the surgeries "some patients continued to experience residual pain at the donor site and rated the appearance of the site as only fair."

Downplaying Safety Concerns

The company also tried, unsuccessfully, to adopt weaker patient safety rules for a clinical trial testing the effectiveness of Infuse in the cervical spine, a use that remains unapproved and which has been linked to life threatening swelling in the neck.

In 2008, the FDA warned doctors against using Infuse in cervical spine fusions, citing 38 cases of swelling in the neck and throat leading to compression of the airway. Some of those cases required emergency tracheotomies.

The weaker safety rules sought by Medtronic would have allowed the company to continue the clinical trial even if patients experienced severe swelling in the neck.

Infuse is a powerful biological agent that stimulates the growth of new bone, but excess bone growth can be a serious problem when the product is used in certain off-label surgeries. It was approved in 2002 for lumbar spine fusions in which the surgical approach is from the front.

The unapproved use has caused serious problems for Patricia Caplinger and hundreds of other spine surgery patients like her, according to a lawsuit filed earlier this year against Medtronic in federal court in Oklahoma.

The complication experienced by Caplinger was the subject of a 2004 paper written by doctors who have received millions of dollars from Medtronic. That paper involved a clinical trial of Infuse that had to be halted 5 years earlier because of excess bone growth in the spinal canals of 70% of the patients.

That clinical trial used Infuse in a surgery similar to what Caplinger underwent in 2010.

The surgeons who wrote the article said that patients weren't harmed by the excess bone growth. But that claim that was refuted by an Oklahoma surgeon who took part in the trial and told the Journal Sentinel/MedPage Today last year that he had two patients who developed painful, excess bone growth that required additional surgeries. Caplinger who lives in Missouri was not one of those patients.

A Helping Hand in the OR

Caplinger says that her doctor and others surgeons were persuaded by Medtronic and its "paid physician promoters" to use Infuse in dangerous, off-label surgeries, according to her lawsuit.

In Caplinger's case, a Medtronic representative actually was present during her surgery and "was actively involved," providing information about use of Infuse in Caplinger's procedure, according to the lawsuit.

Because of the excess bone growth, Caplinger suffers continuous pain in her back and legs and developed a condition known as foot drop, which, in turn, led to a ligament tear in her right knee. She also has required revision surgery on her back and will need another revision surgery because the bone growth is continuing.

In an email, Caplinger, a nurse, said she is worried that the pain eventually will prevent her from doing what she loves the most, working in the emergency department.

"I live with pain every minute of every day," she said. "I have forgotten what not being in pain feels like."

A Medtronic spokesperson said the complaint lacks substance and the company has petitioned the court to dismiss it.

Medtronic Had Answers

The Senate report and accompanying documents also show Medtronic employees -- in addition to editing drafts of a paper -- at times covertly drafted responses to questions raised by other doctors who were examining the work as part of medical journal peer review.

Case in point: A 2004 paper was published in the Spine Journal where co-author Charles Branch Jr., MD, also served as deputy editor. Branch, chairman of neurosurgery at Wake Forest University, received $3.1 million from Medtronic from 1998 to 2010. His royalty payments have been split with the university.

That article also was subject of a 2011 Journal Sentinel/MedPage Today investigation.

The Senate documents include a 2003 email, as the article was being drafted, in which Bill Martin, the company's vice president of spinal marketing, wrote: "We may want to steer clear of calling it a flawed technique. There are still quite a few surgeons utilizing this technique..."

About a week later, Rick Treharne, another Medtronic executive, wrote to one of the paper's authors: "In looking over the data, I was impressed with how well the BMP (Infuse) patients actually did. So much so that I added a few paragraphs at the end that you may not agree with."

As peer reviewers for the journal looked over the paper, they raised concerns that it was a slanted, advertising piece.

"This manuscript is full of biased statements that are a reflection of the data evaluators -- the company that markets the product," wrote one reviewer.

"Unless the authors can discuss the results in this study in an unbiased manner, which they have been unable to do in its present form, this data should not be published," wrote another.

Treharne then sent one of the co-authors a draft of a letter to be sent to the editor of the journal addressing the concern. Another Medtronic executive also helped formulate a response to the editor.

The letter that ultimately was sent to the journal's editor sought to reassure him, claiming that three of the co-authors were independent, the Senate investigation found.

But between 1997 and 2003, two of the "independent" authors had received $8.5 million from Medtronic.

"We were falsely reassured that there were independent people looking at the data," said Eugene Carragee, MD, who took over as editor of the Spine Journal in 2009. "It's a violation of the fundamental trust of peer review."

When published, the paper described the results of halted clinical trial as "encouraging."

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Christopher Snowbeck writes

Medtronic's Covidien deal spurs debate about corporate taxes

Is Medtronic's massive international corporate merger a billion-dollar tax dodge, an indictment of the U.S. tax code, or a business-savvy work-around that would spur investment and growth in the Twin Cities?

The answer depends on who you talk to.

The $42.9 billion cash-and-stock purchase of Covidien, announced Sunday, comes with plans for Medtronic to decamp its executive suite to Ireland, where Covidien is based.

It also will nearly double the size of the Fridley-based medical device maker, and likely result in no significant change in its 8,000-strong Twin Cities workforce. The company is talking about adding 1,000 workers locally.

The move is designed to allow Medtronic to avoid U.S. corporate tax rates in repatriating foreign earnings and cash held overseas, potentially letting the company invest billions in the United States.

But critics questioned whether Medtronic would unfairly shift its tax burden to others. Some questioned whether the move will diminish Medtronic's role in Minnesota, where it's been central to a 50-year local narrative of innovation and business development.

Minnesota politicians of both stripes were critical.

"This clearly highlights the need to fix our broken tax code so American companies can be more competitive," said Republican U.S. Rep. Erik Paulsen. A statement from the Minnesota GOP blamed a medical-device tax associated with Obamacare.

And U.S. Sen. Al Franken, a Democrat, said: "Deals that result in companies reincorporating abroad often mean that they can shelter profits overseas, costing taxpayers billions of dollars -- which I find troubling."

Under the merger agreement announced Sunday, Medtronic Chief Executive Officer Omar Ishrak would lead the merged company, with operational headquarters remaining in Fridley. Principal executive offices would move to Ireland, where Medtronic already has operations.

Different countries impose different tax rates on corporations, and the disparity has prompted firms in high-tax nations to consider these so-called "inversion" deals for many years.

The United States has one of the world's highest corporate tax rates at 35 percent, while Ireland's is relatively low at 12.5 percent, said Ken Levinson, a partner with Faegre Baker Daniels LLP in Minneapolis who leads the firm's international tax practice.

Pulling off an inversion isn't easy.

It Medtronic's shareholders, for example, wind up owning 80 percent or more of the new holding company, the U.S. government wouldn't recognize the new entity as a foreign company, Levinson said, no matter where its executives are based.

The government would decide Medtronic had simply "substituted a different mailbox," he said, and would subject the holding company to regulatory requirements and treatment as a U.S. corporation for tax purposes.

If Medtronic shareholders obtain at least 60 percent of the new holding company, it must pay tax on what's called an "inversion gain" to Internal Revenue Service, Levinson said, and will be subject to certainly regulatory compliance requirements for about 10 years. But up-front costs in that scenario could make sense for the company considering in long-run tax savings, he said.

"In the Covidien transaction, the prior Covidien shareholders would own 30 percent of the resulting equity," Levinson said. "(The companies) have taken pains to fall below the 80 percent threshold -- and they are apparently going to be above the 60 percent threshold."

If Medtronic avoids taxes through an inversion, is that unfair to other U.S. taxpayers?

"Fair or unfair is in the eyes of the policymakers, which changes from time to time," Levinson said. "There have been a number of these transactions over the years. You can see where this makes economic sense."

Last year, Medtronic had about $20.5 billion in undistributed earnings from non-U.S. subsidiaries. It's unclear whether U.S. taxes are owed on the sums, but if so, the merger might provide a chance to get out from under the burden, said Matt Gardner of the Institute on Taxation and Economic Policy, in Washington, D.C.

The Covidien deal could lighten the company's tax burden going forward, Gardner said, adding: "In the long run, we'll all have to pay higher taxes to pay for what Medtronic is doing."

But Medtronic spokesman Rob Clark said such comments mischaracterize the deal. There's no change to the U.S. taxes Medtronic is currently paying, he said, and much of the profit sitting overseas still will be subject to U.S. taxes.

During a conference call with stock analysts Monday, Chief Financial Officer Gary Ellis said the merger "provides us the opportunity to significantly increase our flexibility on the cash side, especially for what capital we can invest back in the United States."

Medtronic's proposal is not unlike the current structure for Covidien, said Brooks West, a stock analyst with Piper Jaffray in Minneapolis. Covidien is based in Ireland, but decision-makers work from a headquarters in Massachusetts.

Medtronic has made assurances that Minnesota will play a key role in the company's future operations, and could see 1,000 new jobs over the next five years.

"I really would be shocked to see much of an employment risk just from Medtronic being domiciled in Ireland," West said. "Minneapolis has got a great base of med-tech talent ... I would be really surprised to see a shift."

Christopher Snowbeck can be reached at 651-228-5479. Follow him atwww.twitter.com/chrissnowbeck.

http://www.twincities.com/business/ci_25975280/medtronics-covidien-deal-spurs-debate-about-corporate-taxes?

BMJ article on The Medtronic Affair

US firm accused of manipulating journal articles and paying millions to authors

The US medical device company Medtronic was “heavily involved in drafting, editing, and shaping the content of medical journal articles authored by its physician consultants,” who were paid hundreds of millions of dollars by the company through royalties and consulting fees, a US Senate Finance Committee staff investigation has found.1

The committee investigated 13 journal articles related to Medtronic’s product Infuse, a bone growth stimulating protein approved by the US Food and Drug Administration (FDA) in 2002 for use in spinal fusion surgery.2 The protein is used in conjunction with a Medtronic spinal fusion device for treatment of degenerative disc disease in the lower spine.

The protein, a genetically engineered version of bone morphogenetic protein 2 (rh-BMP2), has been used to treat more than 500 000 patients. In Europe it is known as dibotermin alfa and it is marketed under the trade name InductOs.

According to the report, Medtronic employees inserted language into medical journal articles that promoted the product without disclosing to the journals “the company’s significant role in authoring or substantively editing” the manuscripts. The company paid “approximately $210m (£130m; €163m) to physician authors of Medtronic sponsored studies from November 1996 through December 2010,” the report alleges.

The report also claims that Medtronic employees sought to downplay adverse events associated with the product while emphasising problems with competing procedures.

In a statement released with the report, committee chairman Senator Max Baucus, a Montana Democrat, said Medtronic’s actions had “violated” patients’ trust.

“Medical journal articles should convey an accurate picture of the risks and benefits of drugs and medical devices, but patients are at serious risk when companies distort the facts the way Medtronic has,” Baucus said.

In a statement, the company disputed the committee staff’s findings. “Medtronic vigorously disagrees with any suggestion that the company improperly influenced or authored any of the peer-reviewed published manuscripts discussed in the report, or that Medtronic intended to under-report adverse events.”3

The company also called the report’s characterisation of the company’s payments to physicians “misleading and unfair.”

“The vast majority of such payments were royalty payments made to compensate physicians for their intellectual property rights and contributions, not consulting payments,” a practice that is “commonplace and appropriate in the medical device industry,” the company said.

However, the company said it agreed with “many of the recommendations in the staff report to ensure increased transparency for industry interactions with physicians.”

In reaction to the report, Michael Heggeness and Charles Mick, president and first vice president of the North American Spine Society, applauded the committee report. The Society’s journal, Spine Journal, published a series of papers in June 2011 challenging the validity of the industry sponsored rh-BMP2 studies.4

“If surgeons had known that the lead authors of the 13 original studies on InFuse had received payments ranging from $1.7m to $64m from Medtronic and that its marketing employees were co-authors and co-editors, would they have been as eager to use InFuse on their patients?” they asked.

Notes

Cite this as: BMJ 2012;345:e7299

http://www.bmj.com/content/345/bmj.e7299

Medtronic pays $40 million to settle kickback suits

Great back story here. Now read on:

Medical device maker Medtronic has agreed to pay $40 million to settle civil allegations that it paid kickbacks to doctors.

The allegations centered around its Memphis, Tenn.-based subsidiary Medtronic Sofamor Danek, which makes implants used in back surgery to stabilize a patient's spine.

The government said that between 1998 and 2003, Medtronic paid kickbacks to doctors, including sham consulting fees, bogus royalty payments, and trips to tourist destinations.

Medtronic said it has entered a five-year agreement to strengthen employee training and compliance programs for its sales and marketing practices.

The federal investigation began with a whistleblower lawsuit. Two such lawsuits are pending. The first, filed in 2002, remains sealed, according to Memphis attorney Andrew R. Carr Jr.

His client, Jacqueline Kay Poteet, filed a second whistleblower lawsuit in 2004. Poteet, a former employee of Medtronic Sofamor Danek, made travel arrangements for doctors to company conferences.

Her lawsuit alleged that Medtronic paid millions of dollars to more than a dozen doctors nationwide, prompting them to perform unnecessary spinal surgeries and otherwise affecting their judgment. One surgeon was allegedly paid $400,000 for eight days of consulting per year.

Another received $1.39 million from 2001 through May 2005, according to the lawsuit.

She alleged the payments were used to induce doctors to use Medtronic products and to recruit other doctors to do the same.

Medtronic said the settlement called for the government to seek the dismissal of both lawsuits.

Carr said the whistleblower statute permits that, but he said he would oppose dismissal of his case because he doesn't believe its allegations are exactly the same as the first, sealed case. He said that case has been described to him but that he doesn't know its details.

Usually, whistleblowers are entitled to a portion (often 10 - 30%) of the money from a settlement. But in this case, Medtronic said the $40 million would be paid into an escrow account and eventually to the Department of Justice.

Carr has said he'll fight any federal effort to keep a portion of the settlement money from his client.

Source: AP

Medtronic Sued by 1,000 Infuse Patients

by John Fauber

Medtronic said about 1,000 people have sued the company over its bone morphogenetic protein-2 (BMP-2) product, Infuse, and that many more lawsuits may be coming.

In addition, several states now are looking into sales and marketing practices involving Infuse, which is used in spine surgery.

In a statement, company spokesperson Cindy Resman said the cases are in early procedural stages, and none have resulted in a finding of liability against Medtronic.

Some court rulings have led to dismissals and others have limited claims.

"Medtronic stands behind Infuse bone graft and will vigorously defend it in court," she said.

Richard Deyo, MD, a professor of family medicine at Oregon Health & Science University, who has done research into the use of Infuse in spine surgeries, said the lawsuits reminded him of other touted medical products that came on the market only later to be found to be harmful to patients -- products like Merck's COX-2 inhibitor, rofecoxib (Vioxx) and Johnson and Johnson's DePuy Synthes artificial hip.

With Infuse, some of the cases may be attorneys drumming up business, but some represent patients who were harmed, Deyo said.

"My cynical view is that companies view this as the cost of doing business," he said.

The patient lawsuits, which were detailed in a recent securities filing by the company, are the latest development in a decade-long saga of a product that has been at the center of investigations, both scientific and legal, as well as a long list of conflict-riddled research done by physicians who received millions of dollars in royalties from Medtronic, while publishing highly favorable articles about Infuse.

"This is a snowballing effect," said Eugene Carragee, MD, head of spine surgery at Stanford University.

Carragee, editor-in-chief of the Spine Journal, which published its own critical review of BMP-2 in 2011, said the lawsuits represent "a whole lot of people" who got a product that never really showed that it was more beneficial than methods used in traditional spinal fusion surgery.

Over the course of 15 years, Medtronic paid $210 million to a group of 13 doctors and two corporations linked to doctors, including more than $34 million to University of Wisconsin orthopedic surgeon Thomas Zdeblick, who co-authored a series of papers about the product.

In addition to the Spine Journal review, there was a damning 2012 U.S. Senate Committee on Finance investigation of Infuse that was started in part because of Journal Sentinel-MedPage Today stories. The finance committee concluded that Medtronic executives secretly drafted some of those favorable journal articles.

In 2013, two independent reports found that Infuse offered little benefit over conventional spine surgery and raised questions about the possibility that the product was linked to serious adverse events including cancer and sterility in men.

The product also can cause the growth of unwanted bone.

In its securities filing, Medtronic said that at the end of its fiscal third quarter of 2014 about 700 lawsuits involving about 1,000 people had been filed over Infuse in state and federal courts.

It also said that law firms have told the company that a large number of similar claims may be brought in the future.

The company said it had not recorded any expense related to potential damages from the lawsuits.

"Additionally, the company cannot reasonably estimate the range of loss, if any, that may result from these matters," it said.

In addition, the company said it has received subpoenas or document requests from government bodies, including civil investigations from state attorneys general in Massachusetts, California, Oregon, Illinois, and Washington.

"The company is fully cooperating with these requests," the Medtronic said.

Also in the SEC filing the company said it expects continued scientific and clinical research scrutiny focused on the safety and efficacy of Infuse in real-world, clinical experience.

Infuse is a biologic agent that stimulates bone growth and has been implanted in the spines of more than 1 million people, most of whom got it in unapproved ways, or so-called off-label use. As much as 85% of BMP-2 use has been off label.

At its height, the product generated sales of $800 million a year, though sales have declined substantially since 2011.

"When you start using a product 85% off label, there are going to be problems," said Dan Spengler, MD, a Vanderbilt University orthopedic surgeon.

Spengler said he suspected that many of the lawsuits involved patients who experienced excess bone growth that occurred after an off-label surgery.

John Fauber received the Association for Medical Ethics Award for Outstanding Achievement in Journalism and Advancing Transparency in Medicine for his reporting on Infuse and other conflicts of interest in medicine.

http://www.medpagetoday.com/Surgery/Orthopedics/44607?isalert=1&uun=g32373d862R5031889u&utm_source=breaking-news&utm_medium=email&utm_campaign=breaking-news&xid=NL_breakingnews_2014-03-04

Researchers get royalties, papers omit sterility link - JSOnline

Since 2002, Medtronic and a group of doctors with financial ties to the medical device company were aware that a new biological agent used in back surgery was linked to sterility in men.

But that crucial information was not revealed in medical journal articles written by those doctors, including surgeons who would receive millions of dollars in various royalties from Medtronic.

Prompted in part by Journal Sentinel stories, independent researchers at Stanford University looking at their own patients have found strong evidence connecting the lucrative product to retrograde ejaculation, a condition that causes sterility in men.

Though original data linking the product to the complication was included in information sent by the company to the Food and Drug Administration as part of the approval process in 2002, those doctors were still claiming there was "no relationship" between the product and the complication as recently as last year.

Medtronic and the doctors contend that the sterility complication was caused by surgical technique, not the product. But professional guidelines and independent doctors contacted by the newspaper say serious complications should be listed in published papers, regardless of what they assume to be the cause.

A new Journal Sentinel analysis found that last year alone Medtronic paid more than $6 million in royalties to a handful of doctors who over the last nine years co-authored papers about the product, known as Infuse, without cautioning that it was linked to male sterility. None of the royalty payments was for Infuse.

One of the authors, Thomas A. Zdeblick, is a University of Wisconsin School of Medicine and Public Health orthopedic surgeon. Zdeblick and Taz Consulting have received more than $23 million in various royalty payments from Medtronic since 2002. Zdeblick also is the editor of the journal where two of the Infuse papers that failed to mention the link were published.

Last year, a Journal Sentinel investigation found that doctors who had financial relationships with Medtronic produced substantially better results with Infuse in the clinical trial leading to its FDA approval than doctors who did not have financial ties to the company.

The newspaper articles documented growing concerns about Infuse side effects and how associated surgeons authored research that has been criticized as little more than marketing.

Meanwhile, Medtronic is under investigation by the U.S. Department of Justice on allegations of off-label marketing of Infuse, a case that could be settled in the near future with civil and criminal penalties, according to a Wells Fargo analyst's report issued last month. Companies are not allowed to promote their products for unapproved, or so-called "off-label," uses.

via jsonline.com

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Medtronic and Mr Polly

By David Armstrong

Did you ever wonder what doctors do to earn big consulting contracts from medical device companies and pharmaceutical concerns?

Records released by Medtronic to Sen. Charles Grassley, a longtime critic of the ties between academics and and health-care companies, provide a rare and detailed glimpse into the daily billings of a consultant — in this case, spine surgeon David Polly of the University of Minnesota.

Polly collected more than $1 million in four years of work for Medtronic, according to the records.

The services he provided were many, but among them, Polly was paid to write articles for medical journals; write a chapter in a book and a book outline; recruit patients for publicity efforts; attend Medtronic national sales meetings; travel to conferences in Japan, Paris and elsewhere; lead training and educational sessions for physicians; and lobby Congress.

Polly also billed for at least two phone calls with Medtronic CEO William Hawkins as well as charging the company $2,000 when Mr. Hawkins visited an operating room. In October, 2003, he billed the company $12,000 for attending a medical meeting of the North American Spine Society, at $4,000 a day.

There are also scores of entries for work billed in five-minute increments, usually to send email or return phone calls. The bill for each five-minute charge? $49.48 a pop.

A lawyer for Polly said the surgeon is also a researcher and consultant, and “works very hard to ensure that he properly tracks and allocates the time spent among these roles and will review any concerns in this area. In every instance, he has conducted himself honorably in advocating for injured veterans.” Medtronic said it’s doing a “comprehensive review” of company procedures aimed at making sure physicians disclose their work for the company and expects to issue new standards in that area.

There is more detail in a WSJ article this morning. Link

Medtronic and Dr Kuklo

Last August, when a British medical journal published a study by five current and former U.S. Army surgeons, the results seemed enormously promising for soldiers who had been maimed in Iraq and for Medtronic Inc.

Probing cases from Walter Reed Army Medical Center, one of the nation's top military hospitals, the article indicated that a Medtronic product that grows and repairs bone could offer a better chance of recovery for soldiers whose legs had been shattered in combat.

Since then, however, an Army investigation has found reason to think that the study overstated the effectiveness of the Medtronic product, inflated the number of patients who were treated and was published without the knowledge of four "co-authors,'' whose signatures were forged.

The case has turned into an embarrassment for Medtronic, which had paid more than $850,000 in fees and expenses to the lead author, Dr. Timothy Kuklo, between 2001 and 2009.

Medtronic says it had no role in the study or knowledge of its publication. But the case has prompted an inquiry by the U.S. Justice Department and Congress, intensifying the scrutiny that has come to bear in the last few years on medical device companies and their financial relationships with doctors.

The Army's wide-ranging investigation provides a rare window into a purported case of medical research fraud.

The article was published in The Journal of Bone and Joint Surgery and written by Kuklo, a highly regarded West Point graduate who retired from the Army in 2006 and is now on the medical faculty at Washington University in St. Louis.

Problems cropped up almost immediately, when a neighbor and fellow physician congratulated Dr. Romney Andersen, an orthopedic surgeon at Walter Reed who was listed as one of four co-authors. Andersen apparently was unaware of the article until that moment.

Source

Medtronic - a night at the ballet, anyone?

Poor Medtronic. Another day another whistleblower suit.

This one looks nailed on as it comes from Jacqueline Kay Poteet, a former employee at the company who made all the bookings and travel arrangements.

When the doctors visited Memphis, she said, Medtronic employees would take them to a local strip club, PlatinumPlus, disguising the expenses as an evening at the ballet.

The suit, which was sealed until Jan. 13, accuses Medtronic of giving spine surgeons "excessive remuneration, unlawful perquisites and bribes in other forms for purchasing goods and medical devices."

A prominent surgeon in Wisconsin was paid $400,000 a year by Medtronic for a consulting contract requiring him to work just eight days. Another doctor in Virginia received nearly $700,000 in consulting fees from Medtronic for the first nine months of 2005.

Read more here

Doctors didn't disclose spine product cancer risk in journal - JSOnline.mobi

Doctors paid millions of dollars by Medtronic failed to identify a significant cancer risk with the company's spine surgery product in a 2009 paper about results of a large clinical trial.

The surgeons left out important data and claimed there was no significant link between the product and cancer.

The company and doctors had become aware of information on an additional cancer case, which pushed the concern to a critical level, at least two months before the paper was published, a Journal Sentinel/MedPage Today investigation found. Independent researchers say they had an ethical duty to report the cancer risk.

The breach is the latest conflict-of-interest controversy facing Medtronic, which is under investigation by a U.S. Senate committee and the U.S. Justice Department for its marketing of the spine surgery product known as bone morphogenetic protein-2, or BMP-2.

The product is the bone growth stimulating biological agent used in the company's Infuse, which has been approved by the U.S. Food and Drug Administration, and Amplify, the unapproved product that was the subject of the 2009 paper.

In June, independent researchers found a systematic failure to report serious complications with BMP-2 in 13 papers published over nearly a decade. The papers were written by doctors who received millions of dollars from Medtronic. The unprecedented rebuke, which was published in the Spine Journal, was prompted in part by stories in the Journal Sentinel.

Medtronic and the lead author of the Amplify paper say there was no "statistically significant" cancer connection to the product at the time the paper was accepted for publication in the Journal of Bone & Joint Surgery . Medtronic also said results from the Amplify clinical trial can't be applied to BMP-2 in general.

The researchers had information showing that at two and three years after being implanted with the genetically engineered protein, significantly higher numbers of Amplify patients were being diagnosed with cancer, but they did not report it on their paper.

The authors mentioned the cancer link only in a table accompanying the paper. The text itself never addressed the concern of whether BMP-2 might fuel cancer.

"As a physician, you go by what your colleagues publish," said Charles Rosen, an orthopedic surgeon and president of the Association for Medical Ethics. "It's an abuse of trust."

via jsonline.mobi

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Medtronic settles shareholder suit over Infuse for $85M - Minneapolis / St. Paul Business Journal

>via bizjournals.com

Medtronic Inc. said Friday it will pay $85 million to settle a shareholders lawsuit that accused the company of making misleading statements about its controversial Infuse spinal product.
Fridley-based Medtronic (NYSE: MDT) said in a news release that it "explicitly denies" that it engaged in any wrongdoing.
The suit was filed in December 2008 by the Minneapolis Firefighters Relief Association, which claimed the company misrepresented Infuse.
The shareholders claimed that Medtronic failed to reveal that as much as 85 percent of Infuse sales depended on sales where doctors would prescribe the product for applications not approved by the U.S. Food and Drug Administration . They also alleged that they were misled about the profitability of Infuse.
Infuse, which promotes bone growth, has been the subject of other criticism over the past year, especially about the way early trials were handled.

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Medtronic Bypasses a Hospital Group Buyer - Duff Wilson, NYTimes.com

Medtronic could save more than $40 million a year through its decision to cancel five group-purchasing contracts worth $2 billion and to negotiate prices directly with hospitals instead, Bernstein Research said in an investor note on Friday.

Whether the hospitals are happy with the move remains to be seen. Novation, the spurned middleman that held the contracts, is certainly unhappy.

Sixteen large hospitals have written Medtronic to express “extreme disappointment,” the group purchasing organization Novation said in a statement Thursday announcing the cancellations. Novation said thousands of hospitals could end up paying higher prices, and would struggle to compare medical devices because of Medtronic pricing confidentiality clauses.

“This move will likely raise costs for member organizations by eliminating the price protection that members benefit from through Novation’s national agreements,” Pete Allen, senior vice president of sourcing operations at Novation, said in a statement.

The hospitals’ letter, dated Feb. 16 and released by Novation on Friday, added, “Neither the health care community nor the country as a whole can afford the type of disruption and increased cost that your decision will have on our facilities.”

via prescriptions.blogs.nytimes.com

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Doctors who endorsed Medtronic product got millions | The Asheville Citizen-Times | citizen-times.com

Doctors who endorsed Medtronic product got millions The Asheville Citizen-Times citizen-times.com

The doctors who did the studies and wrote the articles about Infuse in medical journals received support from Medtronic ranging from $1 million to more than $23 million.

“Can we accept industry-sponsored studies as the basis to go full bore into the use of a product?” said Dr. Dan M. Spengler of Vanderbilt University. “I’m suggesting probably not, based on our experience here.”
Andrew Carr, a lawyer who filed a whistle-blower lawsuit on behalf of former Medtronic employees in Memphis, said the corporate culture within the highly competitive orthopedics industry is at the heart of the problem.

“Sure the culture must change, but that can only change when the penalties, both civil and criminal, become meaningful deterrents,” Carr said. “Otherwise, the continuing hand-slaps and fines will continue to represent the cost of doing business.”

Dept of Irony - Spine Surgeon Sues Spine Surgeon Who Inserted Experimental Artificial Disc in Him

A spine surgeon who was spearheading the development of a new artificial disc decided to use it to help a colleague with back pain. When he inserted the device, the patient's original pain went away but now he had pain in a new area. The patient sued, and the judge in the case ruled the surgeon had failed to follow his own recommendations for inserting the disc. The patient was awarded $650,000 plus legal costs.

Virginia spine surgeon Hallett H. Mathews, MD, was principal investigator for the Maverick, Medtronic's artificial disc that was going through the FDA clearance process at the time. Highly regarded by colleagues, Dr. Mathews had served on the board of directors of the North American Spine Society. When Connecticut spine surgeon Eric M. Garver, MD, told him he was suffering from chronic pain in his back and left leg, Dr. Mathews agreed to personally insert the Maverick disc in him.

The new device made the pain go away, but afterwards Dr. Garver started experiencing pain in a new area on the other side of his body. Patrick Mastroianni, MD, a Connecticut neurosurgeon who operated on Dr. Garver 2 weeks after the original surgery, said he retrieved a bone fragment the size of an olive that was lodged next to the disc and appeared to be pressing against the nerve root in his spine.

Removing the fragment alleviated some of Dr. Garver's pain, but the pain still could not be controlled, even by taking multiple drugs every day. Dr. Garver blamed Dr. Mathews and sued him in state court. Dr. Mathews would not settle the case, insisting he had been careful when inserting the artificial disc and had not violated the standard of care. Furthermore, he disagreed that he had left the bone fragment behind and also questioned whether it was causing the pain.

The judge disagreed with Dr. Mathews's version of the facts and ruled that he had violated his own standard of care. The standard for inserting the Maverick, formulated in part by the defendant himself, required that the disc space be "meticulously cleared of materials that might be driven into nerves behind the disc space by insertion of the artificial disc," the judge wrote.

Thomas Albro, an attorney for Dr. Garver, said Dr. Mathews had helped his client, but only to a point. "He had been suffering significant pain and Dr. Mathews successfully relieved it," the attorney said. "The problem was there was new pain after surgery." Michael Goodman, an attorney for Dr. Mathews, declined to comment.

After years of planning, the Maverick never reached the U.S. market. Before it could complete the FDA clearance process, Medtronic's competitor, Synthes, won a patent infringement lawsuit against Medtronic over the Maverick. Medtronic, which had been selling the Maverick around the world, withdrew it from all markets.

Leigh Page

via outpatientsurgery.net

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Medtronic pay up

Los Angeles Attorney Mychal Wilson Wins Another Fortune 500 Whistleblower Case

SANTA MONICA, Calif., May 29, 2014 /PRNewswire/ -- Qui Tam ("Whistleblower") attorney Mychal Wilson, Esq. announces that Medtronic, the world's largest maker of medical devices, has agreed to pay the United States$9.9 million to resolve allegations under the False Claims Act that the company used various types of payments to induce physicians to implant pacemakers and defibrillators manufactured and sold by Medtronic. This resolution was announced by the United States Department of Justice.

The settlement ends a federal whistleblower suit filed in Eastern District of California by the legal team of Mychal Wilson, Esq. ( www.mychalwilsonesq.com ) and Co-counsels Brooks Cutter and JR Parker of Kershaw, Cutter & Ratinoff, LLP (www.kcrlegal.com ).

Attorney Wilson said, "I would like to thank and congratulate our courageous and conscientious client for bringing justice on behalf of the United States government. We owe this individual an enormous amount of gratitude and respect. Additionally, I would like to thank our legal team, including certified fraud examiner Andy Prough, the Justice Department's Civil Division (attorney Adam Schwartz), the U.S. Attorney's Office for the Eastern District of California (attorney Catherine Swann and her staff, fraud expert David Poulson and paralegal Cassie Christensen), our expert cardiologists, and healthcare industry informants for the great teamwork."

Attorney Mychal Wilson said, "This settlement is a landmark for exposing this issue against a leading medical device company. It's very important that patients ask their physicians if they have received any money or anything of value from pharmaceutical or medical device companies. Especially, as alleged in this matter, for receiving kickbacks such as tickets to sporting events or for referral business in violation of the Federal False Claims Act. These type of improper business arrangements in the practice of medicine need to immediately cease. Not only do kickbacks put patients in harm's way, but they cause false claims for the implantation of Cardiac Rhythm Disease and Management ("CDRM") devices to be submitted to Medicare and Medicaid, which wastes American taxpayer dollars."

"Essentially, you may want to seek a second or even a third opinion before committing to any invasive surgery," said attorney Wilson, a former pharmaceutical rep turned successful whistleblower in the 2007 $515 million DOJ settlement against the pharmaceutical industry giant Bristol-Myers Squibb ("BMS") which inspired him to fight for the rights of other whistleblowers (United States ex rel. Wilson v. Bristol-Myers Squibb, Civil Action No. 06-12195-NG) (D. Mass).

"As an experienced former BMS cardiovascular and diabetes pharmaceutical sales representative, I have witnessed that kickbacks such as tickets to sporting events are often provided to physicians to induce drug prescriptions. I learned that improper financial incentives to prescribe drugs or implant medical devices potentially cloud the sound medical judgment of the physician," argues Wilson.

Attorney Wilson says, "Along with resources such as the Physicians Payment Sunshine Act, patients should check to see if their healthcare provider has received payments or items of value from drug and/or device companies. In today's digital world, patients can cross-check medical references on websites sites likewww.propublica.org ."

This settlement is the result of a coordinated and collaborative investigation between the legal team of Mychal Wilson, Esq., Co-counsels Brooks Cutter and JR Parker of Kershaw, Cutter & Ratinoff, LLP, certified fraud examiner Andy Prough, expert cardiologists, healthcare industry insiders coupled with the Justice Department's Civil Division (attorneys Jamie Yavelberg and Adam Schwartz), the U.S. Attorney's Office for the Eastern District of California (attorneys Benjamin Wagner and Catherine Swann and staff fraud expert David Poulson and paralegal Cassie Christensen), California Deputy Attorney General (attorneys Brian Frankel, Adelina Berumen and Erika Hiramatsu), the Office of Inspector General at the U.S. Department of Health and Human Services and the FBI.

The lawsuit is captioned United States ex rel. Schroeder v. Medtronic, Inc., No. 2:09-cv-0279 WBS EJB (E.D. Cal.).  The claims settled by this agreement are allegations only, and there has been no determination of liability.

Attorney Mychal Wilson has a growing Qui Tam Law practice with several ongoing cases under investigation. Mychal Wilson, Esq. is a member of the State Bar of California and the Qui Tam bar Taxpayers Against Fraud ( http://www.taf.org ). Additionally, Mychal Wilson is an entertainment attorney and media personality who serves as a legal analyst national television.

Big Pharma's Corporate Integrity Agreements

Allergan, Inc. AstraZeneca LP AstraZeneca Pharmaceuticals LP Aventis Inc. et al. and Addendum to the Corporate Integrity Agreement (see also Sanofi-Aventis U.S. Inc.) Boston Scientific Corporation Bristol-Myers Squibb Company Cell Therapeutics, Inc. Cephalon, Inc. CVS Caremark Corporation Depuy Orthopaedics, Inc. Forest Laboratories, Inc. Ivax Corporation ivax Pharmaceuticals, Inc. Jazz Pharmaceuticals, Inc. King Pharmaceuticals, Inc. Medco Health Solutions, Inc. Medicis Pharmaceutical Corporation Medtronic, Inc. Medtronic Sofamor Danek U.S.A., Inc. Medtronic Spine, LLC Novartis Pharmaceuticals Corporation Omnicare, Inc. Omni Healthcare, P.A. Ortho-McNeil-Janssen Pharmaceuticals, Inc. Pfizer Inc. Purdue Pharma L.P. Sanofi-Aventis U.S. Inc., et al. and Addendum to the Corporate Integrity Agreement (see also Aventis Inc.) CIA Addendum to Schering-Plough Corporation Serono Holdings, Inc. SmithKline Beecham Corporation (d/b/a GlaxoSmithKline) CIA Addendum to SmithKline Beecham Corporation (d/b/a GlaxoSmithKline) Smith & Nephew, Inc. Zimmer, Inc.

http://oig.hhs.gov/fraud/cia/cia_list.asp

Hat tip: Stephany

AllTrials contd. - Harlan Krumholz writes

Give the Data to the People

LAST week, Johnson & Johnson announced that it was making all of its clinical trial data available to scientists around the world. It has hired my group, Yale UniversityOpen Data Access Project, or YODA, to fully oversee the release of the data. Everything in the company’s clinical research vaults, including unpublished raw data, will be available for independent review.

This is an extraordinary donation to society, and a reversal of the industry’s traditional tendency to treat data as an asset that would lose value if exposed to public scrutiny.

Today, more than half of the clinical trials in the United States, including many sponsored by academic and governmental institutions, are not published within two years of their completion. Often they are never published at all. The unreported results, not surprisingly, are often those in which a drug failed to perform better than a placebo. As a result, evidence-based medicine is, at best, based on only some of the evidence. One of the most troubling implications is that full information on a drug’s effects may never be discovered or released.

Even when studies are published, the actual data are usually not made available. End users of research — patients, doctors and policy makers — are implicitly told by a single group of researchers to “take our word for it.” They are often forced to accept the report without the prospect of other independent scientists’ reproducing the findings — a violation of a central tenet of the scientific method.

To be fair, the decision to share data is not easy. Companies worry that their competitors will benefit, that lawyers will take advantage, that incompetent scientists will misconstrue the data and come to mistaken conclusions. Researchers feel ownership of the data and may be reluctant to have others use it. So Johnson & Johnson, as well as companies like GlaxoSmithKline and Medtronicthat have made more cautious moves toward transparency, deserve much credit. The more we share data, however, the more we find that many of these problems fail to materialize.

In 2011, YODA struck a deal with Medtronic to release all the data on one of its products — a device that stimulates the production of bone. At the time, questions had been raised about the device’s safety, including whether it caused cancer, and about the conflicts of interests of some of the company’s researchers. Medtronic made the unusual decision to respond to the debate by releasing the device’s data for independent review. We commissioned and then published two independent reviews of the data, and now have made them globally available.

Interestingly, the reviews produced somewhat conflicting results. One found that the device was no better than a bone graft and might be associated with a slight increase in cancer, while the other found that the device was effective and the cancer risk inconclusive. To us these differences reinforce the value of open science: now the data are out there for further study.

This program doesn’t mean that just anyone can gain access to the data without disclosing how they intend to use it. We require those who want the data to submit a proposal and identify their research team, funding and any conflicts of interest. They have to complete a short course on responsible conduct and sign an agreement that restricts them to their proposed research question. Most important, they must agree to share whatever they find. And we exclude applicants who seek data for commercial or legal purposes. Our intent is not to be tough gatekeepers, but to ensure that the data are used in a transparent way and contribute to overall scientific knowledge.

There are many benefits to this kind of sharing. It honors the contributions of the subjects and scientists who participated in the research. It is proof that an organization, whether it is part of industry or academia, wants to play a role as a good global citizen. It demonstrates that the organization has nothing to hide. And it enables scientists to use the data to learn new ways to help patients. Such an approach can even teach a company like Johnson & Johnson something it didn’t know about its own products.

For the good of society, this is a breakthrough that should be replicated throughout the research world.

http://www.nytimes.com/2014/02/03/opinion/give-the-data-to-the-people.html?&_r=0

Medtronic's SynchroDead

Federal health officials said Monday that an implantable drug pump that Medtronic Inc. recalled this year had a potentially life-threatening design problem.

The pump, called the SynchroMed II, delivers drugs directly into the spinal fluid to treat chronic pain and spasticity. The problem relates to the formation of a film within the pump's battery that could hurt the battery's performance and stop the therapy.

Fridley-based Medtronic recalled the product in July, notifying the Food and Drug Administration, patients and doctors about the issue. At the time, the problem had arisen in 55 cases, including one death due to drug withdrawal, among 139,653 SynchroMed II pump implants worldwide.

The FDA on Monday classified the recall as Class I, which refers to products that have a "reasonable probability" of causing "serious adverse health consequences or death."

http://www.startribune.com/business/129697193.html?

Drug research routinely suppressed, study authors find - JSOnline

Drug research, even from clinical trials sponsored by the federal government, routinely is suppressed, harming patients and increasing health care costs, according to new data highlighting an ethical controversy that continues to plague the field of medicine.

"The current situation is a disservice to research participants, patients, health systems and the whole endeavor of clinical medicine," according to an editorial accompanying the papers published in the British Medical Journal.

Turning up the heat, the journal, in an editorial, posed a remedy that is likely to get the attention of doctors who take part in clinical trial research.

"Concealment of data should be regarded as the serious ethical breach that it is, and clinical researchers who fail to disclose data should be subject to disciplinary action by professional organizations," wrote Richard Lehman of the University of Oxford, and Elizabeth Loder, a BMJ editor.

The BMJ papers are the latest thunderbolts in a gathering storm that has swirled around medicine in recent years. The revelations add to the calls for reform in the field.

"It is grossly unethical and an insult to the integrity of medicine when this is allowed to occur and go unpunished," said orthopedic surgeon Chuck Rosen, president of the Association for Medical Ethics.

From diabetes drugs to spine surgery products, scandals involving concealed data have mounted. Consider the cases of two heart drugs that were the subject of Journal Sentinel stories:

For two years, Schering-Plough, the maker of the popular cholesterol drug Vytorin, sat on the results of a clinical trial showing the drug provided no benefit in improving artery health. During that time the drug was heavily marketed to consumers in TV ads. The situation came to light in 2008 after a congressional investigation was launched.

In 2003, a clinical trial of Multaq, a drug that treated irregular heartbeat, was stopped because more patients who were getting the drug were dying than those who were getting a placebo. However, the study was not published until five years later.

In 2007, an independent analysis of the diabetes drug Avandia found that the drug increased heart attacks and cardiovascular deaths.

Access to evidence

Steve Nissen, the lead author of the analysis, said 35 of the 42 studies he looked at were unpublished and were obtained only because a court case required the drug's maker, GlaxoSmithKline, to turn over the data.

"Had the medical community known about this hazard, Avandia would likely never have become the world's largest selling diabetes drug," said Nissen, chairman of cardiovascular medicine at the Cleveland Clinic. "Our ability to provide the best care for patients is dependent on access to all of the available clinical trial evidence, regardless of whether the study showed favorable results."

While much of the criticism of suppressed medical research has been aimed at drug companies, research data from medical devices also has been delayed, especially when it reflects negatively on a product.

Critics pointed to Medtronic's bone-growth stimulating back surgery product known as Infuse.

Last year, the Journal Sentinel reported that the results of a crucial clinical trial of the product were not published until nearly five years after the trial had to be halted because unwanted bone was growing around the spines of the trial volunteers. The paper was written by surgeons who have received millions of dollars in royalties from other Medtronic spine products.

What's more, the authors of the belated paper downplayed the bone overgrowth, saying it did not harm patients, a claim that was flatly rebutted by a doctor interviewed by the Journal Sentinel.

The doctor, an Oklahoma orthopedic surgeon, said two of his patients who were in the trial had to undergo additional surgery because the bone overgrowth was painfully impinging on nerve roots. One of the patients, a man who was in his 50s at the time, needed three operations - one for the implant, a second to remove the unwanted bone formation, and a third when the additional bone grew back yet again.

Independent research and Journal Sentinel stories since have noted that unpublished data showed that Infuse was linked to a variety of serious complications, including sterility in men and cancer.

'Failure in our field'

The failure of the medical literature to report such findings "has been a major failure in our field," said Eugene Carragee, a Stanford University orthopedic surgeon and editor-in-chief of the Spine Journal. Last year, Carragee spearheaded an unprecedented independent analysis showing that Medtronic and a circle of orthopedic surgeons who have received millions of dollars in royalties from the company systematically have failed to report serious complications with the product.

Carragee said the BMJ analysis and its call for disciplinary action against offending doctors is "an important departure from the historical laissez-faire attitude of the recent past."

A surprising finding in the BMJ analysis was that serious lapses occurred even in clinical trials funded by the National Institutes of Health.

That research showed that less than half of NIH-funded clinical trials were published in a medical journal within 30 months of the completion of the trial and after 51 months, one-third of trials remained unpublished.

While industry-related profit motives may not be a factor in such cases, there are other possible explanations, said senior author Harlan Krumholz, a Yale University professor of medicine and investigative medicine and public health.

Sometimes researchers may get an unexpected finding that contradicts a position they have staked out, he said.

"It is a conflict of their academic beliefs," he said.

At the same time, medical journals may not want to publish negative findings, he said.

A second BMJ paper looked at clinical trials of drugs that already had received at least one Food and Drug Administration approval. In such cases a law requires the reporting within one year of the completion of the trial.

Despite the law, only 163 of 738 such trials, or 22%, had reported the results within a year, the paper found.

Lead author Andrew Prayle, a researcher with the University of Nottingham, said he hoped the finding would spur more researchers to post summaries of the work at the NIH site, ClinicalTrials.govClinicalTrials.gov">ClinicalTrials.gov.

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