Evelyn Pringle February 12, 2008
GlaxoSmithKline recently received greetings from a Congressional Committee, asking the company to explain the findings in a report unsealed last month in a lawsuit which shows that Glaxo knew as early as 1989 that Paxil increased the risk of suicidal behavior in patients by more than 8-fold compared to patients who received a placebo.
In a February 6, 2008 letter, Senator Charles Grassley (R-Iowa), ranking member of the Senate Finance Committee, is asking Glaxo to explain why the American public was never adequately informed of this risk until May 2006 in a "Dear Healthcare Professional" letter which reported a "higher frequency of suicidal behavior" associated with Paxil as compared to placebo.
The report showing the 8-fold suicide risk, by Harvard instructor and psychiatrist Joseph Glenmullen, was unsealed on January 18, 2008, by a federal judge in a US District Court in Sacramento, California in the Paxil suicide case of O'Neal v SmithKline Beecham d/b/a GlaxoSmithKline, filed by the surviving family members of 13-year-old Benjamin Bratt.
Dr Glenmullen was retained as an expert in the case by the California-based Baum, Hedlund, Aristei & Goldman law firm.
On January 30, 2008, the court dismissed the lawsuit on the basis of the Bush Administration's new preemption policy, largely unknown to most Americans, which says that once the FDA approves a drug and its label, citizens may not sue a company for failing to warn about a risk not listed on the label, even in cases like this where the plaintiff can prove that the company knew about the risk and intentionally concealed it.
SSRI's are antidepressants known as selective serotonin reuptake inhibitors and include Paxil, Eli Lilly's Prozac, Zoloft by Pfizer and Celexa and Lexapro marketed by Forest Labs. Wyeth's Effexor, Lilly's Cymbalta and Glaxo's Wellbutrin are not considered SSRI's, but they also carry a warning about an increased risk of suicidality in young people.
Two SSRI suicide cases are now awaiting a joint decision from the Third Circuit Court of Appeals for which oral arguments took place in December 2007.
In the case of Colacicco v Apotex, the US District Court for the Eastern District of Pennsylvania was the first to dismiss a failure-to-warn claim based on the new preemption policy, and in McNellis v Pfizer, the US District Court for the District of New Jersey found no preemption.
Also unbeknownst to most Americans, the Bush Administration is instructing judges to dismiss the lawsuits against the SSRI makers in amicus briefs filed by the government's top attorneys, who also attend hearings when necessary to argue on behalf of the SSRI makers during oral arguments on motions to dismiss.
In fact, in regard to requiring a warning about suicide, during oral arguments in the Third Circuit, Bush Administration attorney Sharon Swingle told the court that the FDA "had again and again and again made an expert determination that the warning was not appropriate."
She maintained that the claims were preempted because the SSRI makers were not allowed to add warnings to the label under any circumstances without prior approval from the FDA.
At one point, the court asked an attorney for an SSRI maker, "assume for the moment that you had reasonable evidence of an association between your product and a serious hazard or a serious possibility of an enhanced suicide risk."
Under federal regulations, "what would be your obligation?"
The attorney stated, "our obligation would be to take that information to the FDA, advise the FDA of the information."
"It then would be the FDA's determination whether that represented a substantial relationship," he told the court.
"So if you had evidence internally that there's an enhanced risk of suicide, you would go to the FDA," the court said, and asked, "And how long would that take?"
"I do not know the answer to that, your Honor," the attorney said, and the court asked, "Could it take months?"
"I imagine it would depend on the seriousness --," the attorney stated.
"But isn't there a significant possibility that additional people then might have the same consequence that happened here with McNellis, or with Colacicco and McNellis's father?" the court asked.
The attorney said, "on the basis of the information that was available we would take it per FDA directive to the FDA and they would make the determination whether the label should be changed."
"Other people could then," the court continued, "possibly have an enhanced risk of suicide and other people may commit suicide as a result of taking your product?"
"We would be bound by law to comply with the FDA, then to comply with its directives," the attorney replied.
"Are they requiring that you go through them first rather than act on your own?" the court asked.
"That's exactly correct, your Honor, because there is the bigger issue of the --" the attorney stated.
However, at the end of the hearing, Pennsylvania attorney Derek Braslow proved beyond any doubt that the claims made by the Bush Administration attorney and the attorneys for the drug makers were blatant lies, when he informed the court that Glaxo had "independently, strengthened their warning in May 2004 to warn about increased suicidality and worsening depression in everyone, not just children."
"There was specifically in bold letters a new warning with respect to increased suicidality and worsening depression in May 2004," he stated.
"Glaxo changed the label on their own without FDA approval," Mr Braslow told the court.
Glaxo did it again in May 2006, he said, when they sent out a "Dear Healthcare Professional" letter and warned about the increased risk of suicidality and suicidal behaviors with Paxil in persons of all ages.
During oral arguments in the O'Neal case on January 21, 2008, Glaxo's preemption argument was presented by King & Spalding attorney Mark Brown, who just happens to be a former Associate Chief Counsel for the FDA from the first Bush Administration.
The family intends to ask the court to reconsider the ruling in the O'Neal case, according to a statement by Baum Hedlund.
In his report, Dr Glenmullen sums up the inadequacy of the system, including the FDA, that allowed Glaxo to keep this vital information hidden from prescribing doctors and patients for nearly 2 decades and states, in part:
"One of the most sobering aspects of the story of Paxil-induced suicidality is that GlaxoSmithKline was not forthcoming with its data demonstrating the risk and regulatory agencies like the FDA did not take the initiative to get to the bottom of and expose the true risk."
"Rather, the impetus came from attorneys and medical experts surprised by what they found in GlaxoSmithKline's confidential documents, which only came to light through litigation."
"The GlaxoSmithKline documents that have so-far made it into the public record have in turn been critical to educating patients, the public, and the media about the true risk. The media - particularly the BBC in England - played a crucial role in turning the tide in the history of Paxil-induced suicidality."
According to Dr Glenmullen, "it was the diligent efforts of plaintiff's attorneys that forced GlaxoSmithKline to divulge the inaccurate counting method to the FDA."
Another leading expert on pharmacology, Dr Peter Breggin, warns that an 8-fold increased risk of suicidality in controlled clinical trials could mean 80-fold in actual practice. "We can't determine exactly how much greater the risk will be in clinical practice but it will be astronomically greater," he advises.
In actual practice, he explains, many patients are already suicidal when they start taking the drug, increasingly the likelihood that the drug can push them over the edge.
Despite the warnings to watch patients closely, Dr Breggin says, busy doctors do not monitor patients properly. He explains that they are almost never evaluated for suicidality and are often given multiple drugs at the same time, by doctors who know little about their adverse effects on the mind.
Glaxo is facing lawsuits from surviving family members of Paxil suicide victims all over the country and is attempting to use preemption to avoid public trials for good reason. The first case to go before a jury in Wyoming in 2001, involved a man who shot his wife, daughter and infant granddaughter before shooting himself after being on Paxil for just a matter of days.
The trial resulted in a verdict against Glaxo for $6.4 million after the jury weighed the expert testimony of famed pharmacologist Dr David Healy, who presented a summary of Glaxo's hidden suicide data on Paxil, against the testimony of the industry-funded SSRI defender Dr John Mann, whose name appears on many of the studies issued over the years, some as late as 2007, that steadfastly proclaim that SSRI's are not linked to suicide and should be prescribed to children.
In addition to Dr Healy's revelations about hidden data showing that Glaxo was aware of the increased risk, Dr Mann's credibility was likely weighed against the fact that he had received over $30 million in research funding from drug companies between the early 1990's and the trial in 2001, which was brought out during his testimony by Houston attorney Andy Vickery.
Mr Vickery also established that, roughly 10 years and $30 million earlier, Dr Mann had published a paper stating that SSRI's could increase suicidality in a small subset of patients.
In his report, Dr Glenmullen states that, since Glaxo had the original data in 1989 that showed a greater than eightfold increased risk, it should have warned doctors and patients about the risk "a decade-and-a-half ago when Paxil was first approved by the FDA."
The report includes portions of an April 29, 1991 report, written by Glaxo psychiatrist Dr Geoffrey Dunbar, sent to the FDA in response to a specific request for information on suicidality in which Glaxo openly lies in stating: "analyses of our prospective, clinical trials for depression show that patients who were randomized to Paxil therapy were at no greater risk for suicidal ideation or behavior than were patients randomized to placebo or other active control therapies."
Dr Glenmullen notes the importance of the date that this false data was submitted because the FDA had scheduled a hearing with a nine-member advisory panel for September 20, 1991, to discuss concerns raised a year earlier about the possibility of Prozac making patients suicidal. Paxil was not approved for use in the US until December 2002.
In his report, Dr Glenmullen points out that 5 of the 9 members on the advisory panel had conflicts of interest with drug makers and that 2 psychiatrists, Dr David Dunner of the University of Washington in Seattle and Dr Stuart Montgomery from England, had done research on Prozac for Eli Lilly, and later played crucial roles in Glaxo's publishing of what he calls "bad" suicide numbers in the Paxil story.
Dr Glenmullen's report includes portions of a September 19, 1991, memo distributed to over 20 senior staff the day before the hearing with a "Statement to be used to respond to inquiries re Paxil/Suicide," which claims explicitly that during GlaxoSmithKline's studies: "the incidence of suicide was lower among patients receiving Paxil than among those receiving placebo."
This was the statement the company ordered employees to make, even though 5 patients on Paxil committed suicide while no patients in the placebo group did. In addition, Dr Glenmullen points out that, up to 1989, seriously suicidal patients were excluded from Glaxo's studies, and therefore "anyone who became seriously suicidal during the studies only became so after being given Paxil or a placebo."
Yet the actual numbers show that there were 40 suicide attempts in the clinical trials by patients taking Paxil compared to 1 suicide attempt in the placebo groups.
Despite the poor quality of the data available to the advisory committee, and despite the many conflicts of interest of its members, one third of the members still voted for a warning in 1991, Dr Glenmullen points out.
Three months later, in December 1991, Dr Dunner, together with Glaxo psychiatrist Dr Dunbar, presented Glaxo's Paxil data with the "bad" numbers at a meeting of the American College of Neuropsychopharmacology (ACNP) in Puerto Rico.
During the presentation, the doctors told the ACNP: "Suicide and suicide attempts occurred less frequently with Paxil than with either placebo or active control," according to the Glenmullen report.
The ACNP's members are considered prominent academic psychiatrists who specialize in pharmacology, and the group has issued a number of position papers over the years which consistently denied a link between SSRI's and suicidality.
Dr Mann led an ACNP task force which included Dr Fred Goodwin, Dr Charles O'Brien and Dr Robinson, which supposedly reviewed all the clinical trial data on SSRI's and issued a consensus statement with the position that SSRI's did not increase the risk of suicidal behavior, which was published in the journal Neuropsychopharmacology in 1993.
In March 1995, Dr Dunner, Dr Montgomery and Dr Dunbar published the paper, "Reduction of suicidal thoughts with paroxetine in comparison with reference antidepressants and placebo," in the European journal Neuropsychopharmacology. This paper included a table with the "bad" numbers and claimed that other antidepressants were more likely to increase the risk of suicide than Paxil.
The paper specifically states: "Consistent reduction in suicides, attempted suicides, and suicidal thoughts, and protection against emergent suicidal thoughts suggest that Paxil has advantages in treating the potentially suicidal patients."
On July 5, 1995, Glaxo's marketing department issued a memo urging its sales force to use the Dunner-Dunbar paper to reassure doctors who were concerned over Paxil-related suicide that there was no need for concern.
The fact is, documents obtained in litigation prove that the FDA has known about the suicide risks of SSRI's for roughly 23 years. Two years before Prozac was approved, in May 1985, the FDA's chief investigator, Dr Richard Kapit, wrote: "Unlike traditional tricyclic antidepressants Fluoxetine's profile of adverse side effects more closely resembles that of a stimulant drug than one that causes sedation."
"It is Fluoxetine's particular profile of adverse side-effects which may perhaps, in the future give rise to the greatest clinical liabilities in the use of this medication to treat depression," he noted.
Dr Kapit's review described data from 46 clinical trials with a total of 1,427 patients and under the section, "Catastrophic and Serious Events," he listed 52 cases of "egregiously abnormal laboratory reports which were the reason for early termination," and "additional adverse event reports not reported by the company were revealed on microfiche."
"In most cases," he wrote, "these adverse events involved the onset of an unreported psychotic episode."
There were ten reports of psychotic episodes including 2 reports of completed suicides, 13 attempted suicides, 4 seizures, and 4 reports of movement disorders. In 1985, Dr Kapit recommended "labeling warning the physician that such signs and symptoms of depression may be exacerbated by this drug".
When Prozac was approved, no such warning was issued.
Two weeks after the FDA advisory panel met in February 2004 to review the data on SSRI's to determine whether they were linked to suicide, Dr Healy sent a report to Peter Pitts, Associate Commissioner for External Relations, at the FDA, in response to an invitation by Dr Robert Temple for a submission of the details of studies referred to in the course of a presentation at the meeting.
"A great number of the patient testimonies in the course of the Feb 2nd hearing were from individuals who became suicidal on an SSRI when their underlying disorder was Lyme Disease, migraine or a condition such as social phobia," Dr Healy pointed out.
He also noted that this had been the case in the 1991 hearings, when it was framed by FDA's Dr Temple as follows:
"The discussion we heard earlier showed that people who commit suicide are highly likely to have a diagnosis of depression, which means that somebody identified them as in a high-risk category. But there were still a significant number of people who committed suicide without having that sort of diagnosis and I guess I would like some advice or discussion on who those people were."
"The anecdotes that one hears that are most evocative to me anyway are not the ones where people who have a 20-year history of suicidal ideation and then finally do it - that is not too surprising - it is where they assert that there has never been anything in their minds like that before and yet now they have suddenly become excessively concerned with suicide and may even do it."
Dr Healy's analysis submitted to the FDA included the data from the pediatric trials on suicidality and hostility, including some that were concealed for years. To distinguish the difference between suicide caused by SSRI's verses suicide caused by the underlying depression, he separated the data on children who were treated for depression and children who were treated for obsessive compulsive disorder or social phobia.
The analysis found that SSRI's can cause some children who are not depressed to become suicidal when taking the drugs for other conditions. From a pool of 931 depressed patients taking SSRI's versus 811 depressed patients taking placebo, Dr Healy determined that there were 52 suicidal acts by patients on SSRI's versus 18 in the placebo group.
In a pool of 638 patients taking SSRI's for other disorders versus 562 patients taking a placebo, there were 10 suicidal acts in the SSRI group versus 1 in the placebo group.
When these data sets were combined, there were 62 episodes of suicidality in the 1,569 patients on SSRI's versus only 19 episodes in the 1,373 patients on a placebo.
In his submission to the FDA, Dr Healy also explained that he had conducted his own trial on Zoloft in 2000 with 20 "healthy volunteers," meaning they had no mental disorder when entering the trial, and two of the Zoloft patients became suicidal. This type of study provides the strongest evidence of drug-induced suicidality because it's impossible for drug companies to claim that a patient became suicidal as a result of the underlying depression.
Seven years ago, during the Wyoming jury trial involving the tragic Paxil-induced murder-suicide, the man's physician testified that he may not have prescribed Paxil if a warning regarding homicide and suicide had been added to the drug's label.
In his report released last month, Dr Glenmullen offers the following heart-wrenching conclusion to the court: "It is my opinion to a reasonable degree of medical probability that if GlaxoSmithKline had provided a warning all these years, Benjamin Bratt would still be alive today."
On April 24, 2004, the Lancet medical journal published an editorial entitled, "Depressing Research," with the following comments that surely ring doubly true today for the Bratt family, as well as all the other families whose children committed suicide while on SSRI's:
"It is hard to imagine the anguish experienced by the parents, relatives, and friends of a child who has taken his or her own life. That such an event could be precipitated by a supposedly beneficial drug is a catastrophe. The idea of that drug's use being based on the selective reporting of favourable research should be unimaginable."
Showing posts with label FDA. Show all posts
Showing posts with label FDA. Show all posts
Sunday, August 8, 2010
More Scrutiny of Stenting for Profit Industry
Evelyn Pringle August 2007
The stenting for profit industry hit a major snag on March 1, 2007, when the US House Oversight and Government Reform Committee, ordered Johnson & Johnson and Boston Scientific to turn over documents related to their sales and marketing activities for drug-eluting stents.
Drug-eluting stents (DES) are mesh tubes used in patients with heart disease to keep arteries open after a procedures called angioplasty to remove blockage. The new drug-eluding stents were developed to address the problem of restenosis, which prevents renarrowing of the artery. The relative benefits of DES when compared to bare metal stents was supposed to be a reduction of death, heart attack and vessel revascularization.
"Since the new DES arrived on the market, stenting has evolved into a multi-billion dollar industry for the stent makers and doctors and hospitals alike. According to the May 17, 2007 Wall Street Journal, "Americans spent at least $14 billion on coronary-stent procedures last year, including surgical and hospital fees."
Both J&J and Boston have received letters from Committee Chairman, Henry Waxman (D-CA), requesting documents to include correspondence with the FDA. The Committee also wants to know whether the companies used marketing funds to conduct clinical trials and how much researchers were paid and seeks information related to any adverse events revealed in the pre-approval clinical trials, as well as in post-approval use of the products.
In May 2007, after J&J announced that it would withdraw the Conor Medsystem's heart stent from the Indian market after the device failed to complete clinical trials in the US, the Drug Controller General of India raided the company's distributor's office in New Delhi and seized all existing stock of the heart stent, India's drug controller general M Venkateswarlu told the Economic Times on May 10, 2007.
The exact number of Conor stents currently on the market was still being assessed but the Times reports that thousands of patients in India could be at risk because an estimated 8,000 Indian patients have be implanted with the device.
Also the recent "Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE),"study published online on March 26, 2007, by the New England Journal of Medicine showed patients who received stents fared no better than patients who did not.
For the study, led by Dr William Boden of Buffalo General Hospital in New York, half of the roughly 2,300 patients underwent stenting procedures, took heart drugs, and were counseled to make lifestyle changes, such as losing weight, exercising, and giving up smoking and the other half received only lifestyle counseling and drugs to lower cholesterol, relax blood vessels, slow heart rate, and prevent blood clots. After an average of four and a half years, the study found a similar rate of death, heart attack, and stroke in both groups.
In an editorial accompanying the NEJM study, Dr Judith Hochman and Dr Gabriel Steg wrote: "The COURAGE trial should lead to changes in the treatment of patients with stable coronary artery disease, with expected substantial health care savings."
Experts note that there are massive profits at stake. In 2006 alone, combined J&J and Boston earned $3 billion from the devices. On December 4, 2006, Bloomberg News reported that in 2005, the new stents accounted for 52% of total sales for J&J and 43% for Boston.
In July 2007, the stent makers announced their second-quarter earnings and J&J revealed that sales of the Cypher in the US have dropped 41% from this time last year, while Boston released sales figures for its Taxus showing a drop of 42%.
In December 2006, an FDA Advisory Panel determined that off-label use, or using a stent for a purpose outside the device's approved label, is associated with an increased risk of stent thrombosis, death or heart attack compared to approved uses.
Some examples of off-label stenting include use in previously stented patients, patients with diabetes, patients who have stents placed immediately after a heart attack or patients who have stents placed in two arteries which branch off from each other.
Experts say that in the majority of cases the devices are being implanted in patients who could potentially be harmed. According to the FDA, over 60% of DES are being implanted in patients with more complex heart problems than the conditions for which the devices were approved.
With a priced tag of $10,000 to $38,000, as many as 85% of the stenting procedures are non-emergency and are being performed on people with only partially blocked arteries for the relief of recurrent chest pain, according to March 23, 2007 Associated Press.
The first DES was approved in April 2003, and by December 2006, at a hearing on the "Prospective on Drug eluting Stents: Balancing Risks and Benefits," the Advisory Panel reported that 3 out of 5 implants were for unapproved uses.
Dr Ron Waksman presented the results for Contemporary Registries of Washington Hospital Center and reported that the rates of stent thrombosis were almost doubled in cases of off-label use compared to on-label use at 30 days and at 12 months.
He also said that in general, when they looked at on-label and off-label use, "the drug eluting stents are more thrombogenic than bare-metal stents."
For both on-label and off-label use, Dr Waksman said, "over time, late stent thrombosis is seen more in the DES versus the bare-metal stents."
Dr Peter Smith of Duke University told the panel that stenting is being performed on patients with high severity coronary problems such as 3 vessel disease who should be undergoing coronary bypass grafting surgery.
He presented data that showed in these types of cases, 1 out of every 20 patients who died after treatment with stenting would have survived if coronary bypass grafting would have occurred and that DES use in patients with 3 vessel disease results in about 3,600 premature deaths annually in the US.
In the end, the panel did recommend that a warning be added to the DES labels stating that off-label use may increase the risk of thrombosis, myocardial infarction, and death, and several members recommended that a black box warning be added. However, Dr Brian Zuckerman, director of the FDA's division of cardiovascular devices, quickly quashed that idea, saying there would be no black box warning, according to MedPage Today on December 8, 2006.
But as usual, investigations have shown that the FDA was aware of the DES problems for years. Within 6 months of the approval of the first DES, the FDA had already identified 50 cases of allergic reactions and agency records show that a few months after the Cypher arrived on the market, the FDA received a cluster of sub-acute thrombosis reports and the FDA and J&J issued a letter notifying doctors of the initial reports in July 2003.
The Tarus was launched in March 2004, and on July 16, 2004, Boston announced a major recall of 85,000 of the devices after a death and serious injuries were linked to the DES, just two weeks after 200 were recalled following reports of malfunctions during implant procedures. At the time of the announcement, the company also said that it was recalling 11,000 bare metal stent systems, which the FDA found to be linked to two deaths and 25 serious injuries.
Two years later on October 23, 2006, Bloomberg reported that 2.9% of DES patients could develop clots within three years and said, "More than 4 million people have received such stents since 2001, which means clotting related to drug-coated devices may have caused as many as 20,000 heart attacks and 10,000 deaths worldwide."
The American College of Cardiology posted an editorial online by Dr Sanjay Kaul, director of the cardiology fellowship training program at Cedars-Sinai Medical Center and a colleague on October 11, 2006, that warned that blood clots in drug-coated stents may be causing an extra 2,160 deaths in the US alone each year.
The next month, on November 29, 2006 analysis by researchers at the Cleveland Clinic found the risk of blood clots was increased as much as 5-fold in patients who receive drug-coated stents compared to patients implanted with the old bare-metal stents.
"There are hundreds of thousands of Americans who are currently getting stents placed who do not need it as initial therapy," according to Dr Raymond Gibbons, professor of medicine at the Mayo Medical School and president of the American Heart Association, in a United Press International article.
In the March 28, 2007, Wall Street Journal Health Blog, Dr Andy Demajio wrote, "It has been distressing to see how interventional cardiologists have been happily stenting their patients to fatten their wallets."
"This immoral practice should come to a stop," he wrote. In May 2007, the Medicare Strike Force reported that one cardiologist had implanted 25 unnecessary stents in 2006 alone, with most procedures paid for by Medicare.
Legal experts are predicting that future lawsuits filed against Boston and J&J may well include the names of cardiologists and hospitals that helped turn the stenting for profit business into a billion dollar industry. Being there is no way to reverse the stenting procedure, patients face a life-time of worry because a blot clot in a stent can cause a stroke or heart attack without warning at any time.
Lawsuits against the stent makers continue to mount. On December 6, 2007, 46-year-old Sean O'Shea, a man who had five stents implanted, announced a lawsuit against J&J, alleging the company failed to warn him about potential blood clotting complications associated with the stents.
"Had I known there would have been this many complications," he said in a news conference, "I would have chosen other options."
On July 30, 2007, the Zimmerman Reed law firm announced the filing of a lawsuit against J&J by a Minnesota man who suffered a heart attack as a result of a blood clot at the site of his Cypher implant. According to the press release, it is estimated that over 50,000 patients have been implanted with the Cypher stent.
The stenting for profit industry hit a major snag on March 1, 2007, when the US House Oversight and Government Reform Committee, ordered Johnson & Johnson and Boston Scientific to turn over documents related to their sales and marketing activities for drug-eluting stents.
Drug-eluting stents (DES) are mesh tubes used in patients with heart disease to keep arteries open after a procedures called angioplasty to remove blockage. The new drug-eluding stents were developed to address the problem of restenosis, which prevents renarrowing of the artery. The relative benefits of DES when compared to bare metal stents was supposed to be a reduction of death, heart attack and vessel revascularization.
"Since the new DES arrived on the market, stenting has evolved into a multi-billion dollar industry for the stent makers and doctors and hospitals alike. According to the May 17, 2007 Wall Street Journal, "Americans spent at least $14 billion on coronary-stent procedures last year, including surgical and hospital fees."
Both J&J and Boston have received letters from Committee Chairman, Henry Waxman (D-CA), requesting documents to include correspondence with the FDA. The Committee also wants to know whether the companies used marketing funds to conduct clinical trials and how much researchers were paid and seeks information related to any adverse events revealed in the pre-approval clinical trials, as well as in post-approval use of the products.
In May 2007, after J&J announced that it would withdraw the Conor Medsystem's heart stent from the Indian market after the device failed to complete clinical trials in the US, the Drug Controller General of India raided the company's distributor's office in New Delhi and seized all existing stock of the heart stent, India's drug controller general M Venkateswarlu told the Economic Times on May 10, 2007.
The exact number of Conor stents currently on the market was still being assessed but the Times reports that thousands of patients in India could be at risk because an estimated 8,000 Indian patients have be implanted with the device.
Also the recent "Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE),"study published online on March 26, 2007, by the New England Journal of Medicine showed patients who received stents fared no better than patients who did not.
For the study, led by Dr William Boden of Buffalo General Hospital in New York, half of the roughly 2,300 patients underwent stenting procedures, took heart drugs, and were counseled to make lifestyle changes, such as losing weight, exercising, and giving up smoking and the other half received only lifestyle counseling and drugs to lower cholesterol, relax blood vessels, slow heart rate, and prevent blood clots. After an average of four and a half years, the study found a similar rate of death, heart attack, and stroke in both groups.
In an editorial accompanying the NEJM study, Dr Judith Hochman and Dr Gabriel Steg wrote: "The COURAGE trial should lead to changes in the treatment of patients with stable coronary artery disease, with expected substantial health care savings."
Experts note that there are massive profits at stake. In 2006 alone, combined J&J and Boston earned $3 billion from the devices. On December 4, 2006, Bloomberg News reported that in 2005, the new stents accounted for 52% of total sales for J&J and 43% for Boston.
In July 2007, the stent makers announced their second-quarter earnings and J&J revealed that sales of the Cypher in the US have dropped 41% from this time last year, while Boston released sales figures for its Taxus showing a drop of 42%.
In December 2006, an FDA Advisory Panel determined that off-label use, or using a stent for a purpose outside the device's approved label, is associated with an increased risk of stent thrombosis, death or heart attack compared to approved uses.
Some examples of off-label stenting include use in previously stented patients, patients with diabetes, patients who have stents placed immediately after a heart attack or patients who have stents placed in two arteries which branch off from each other.
Experts say that in the majority of cases the devices are being implanted in patients who could potentially be harmed. According to the FDA, over 60% of DES are being implanted in patients with more complex heart problems than the conditions for which the devices were approved.
With a priced tag of $10,000 to $38,000, as many as 85% of the stenting procedures are non-emergency and are being performed on people with only partially blocked arteries for the relief of recurrent chest pain, according to March 23, 2007 Associated Press.
The first DES was approved in April 2003, and by December 2006, at a hearing on the "Prospective on Drug eluting Stents: Balancing Risks and Benefits," the Advisory Panel reported that 3 out of 5 implants were for unapproved uses.
Dr Ron Waksman presented the results for Contemporary Registries of Washington Hospital Center and reported that the rates of stent thrombosis were almost doubled in cases of off-label use compared to on-label use at 30 days and at 12 months.
He also said that in general, when they looked at on-label and off-label use, "the drug eluting stents are more thrombogenic than bare-metal stents."
For both on-label and off-label use, Dr Waksman said, "over time, late stent thrombosis is seen more in the DES versus the bare-metal stents."
Dr Peter Smith of Duke University told the panel that stenting is being performed on patients with high severity coronary problems such as 3 vessel disease who should be undergoing coronary bypass grafting surgery.
He presented data that showed in these types of cases, 1 out of every 20 patients who died after treatment with stenting would have survived if coronary bypass grafting would have occurred and that DES use in patients with 3 vessel disease results in about 3,600 premature deaths annually in the US.
In the end, the panel did recommend that a warning be added to the DES labels stating that off-label use may increase the risk of thrombosis, myocardial infarction, and death, and several members recommended that a black box warning be added. However, Dr Brian Zuckerman, director of the FDA's division of cardiovascular devices, quickly quashed that idea, saying there would be no black box warning, according to MedPage Today on December 8, 2006.
But as usual, investigations have shown that the FDA was aware of the DES problems for years. Within 6 months of the approval of the first DES, the FDA had already identified 50 cases of allergic reactions and agency records show that a few months after the Cypher arrived on the market, the FDA received a cluster of sub-acute thrombosis reports and the FDA and J&J issued a letter notifying doctors of the initial reports in July 2003.
The Tarus was launched in March 2004, and on July 16, 2004, Boston announced a major recall of 85,000 of the devices after a death and serious injuries were linked to the DES, just two weeks after 200 were recalled following reports of malfunctions during implant procedures. At the time of the announcement, the company also said that it was recalling 11,000 bare metal stent systems, which the FDA found to be linked to two deaths and 25 serious injuries.
Two years later on October 23, 2006, Bloomberg reported that 2.9% of DES patients could develop clots within three years and said, "More than 4 million people have received such stents since 2001, which means clotting related to drug-coated devices may have caused as many as 20,000 heart attacks and 10,000 deaths worldwide."
The American College of Cardiology posted an editorial online by Dr Sanjay Kaul, director of the cardiology fellowship training program at Cedars-Sinai Medical Center and a colleague on October 11, 2006, that warned that blood clots in drug-coated stents may be causing an extra 2,160 deaths in the US alone each year.
The next month, on November 29, 2006 analysis by researchers at the Cleveland Clinic found the risk of blood clots was increased as much as 5-fold in patients who receive drug-coated stents compared to patients implanted with the old bare-metal stents.
"There are hundreds of thousands of Americans who are currently getting stents placed who do not need it as initial therapy," according to Dr Raymond Gibbons, professor of medicine at the Mayo Medical School and president of the American Heart Association, in a United Press International article.
In the March 28, 2007, Wall Street Journal Health Blog, Dr Andy Demajio wrote, "It has been distressing to see how interventional cardiologists have been happily stenting their patients to fatten their wallets."
"This immoral practice should come to a stop," he wrote. In May 2007, the Medicare Strike Force reported that one cardiologist had implanted 25 unnecessary stents in 2006 alone, with most procedures paid for by Medicare.
Legal experts are predicting that future lawsuits filed against Boston and J&J may well include the names of cardiologists and hospitals that helped turn the stenting for profit business into a billion dollar industry. Being there is no way to reverse the stenting procedure, patients face a life-time of worry because a blot clot in a stent can cause a stroke or heart attack without warning at any time.
Lawsuits against the stent makers continue to mount. On December 6, 2007, 46-year-old Sean O'Shea, a man who had five stents implanted, announced a lawsuit against J&J, alleging the company failed to warn him about potential blood clotting complications associated with the stents.
"Had I known there would have been this many complications," he said in a news conference, "I would have chosen other options."
On July 30, 2007, the Zimmerman Reed law firm announced the filing of a lawsuit against J&J by a Minnesota man who suffered a heart attack as a result of a blood clot at the site of his Cypher implant. According to the press release, it is estimated that over 50,000 patients have been implanted with the Cypher stent.
FDA Officials Form Hit Squad to Protect Avandia Profits
Evelyn Pringle August 2007
The FDA's latest campaign to protect the profits of a drug company over the safety of Americans is unprecedented, and the organizers include a gang of current and former FDA officials largely credited with turning the nation's regulatory beagle into a lapdog for Big Pharma under the Bush Administration.
FDA spokesman Douglas Arbesfeld, apparently the industry's new inside guy, kicked off the campaign by sending an e-mail to journalists which was intended to discredit Dr Steven Nissen and the Cleveland Clinic. Dr Nissen's study appeared online on May 21, 2007, in the New England Journal of Medicine and warned that GlaxoSmithKline's diabetes drug Avandia increased the risk of heart attacks by 43% and death from cardiovascular events by possibly 64%.
The talking points for the media were obviously agreed upon ahead of time because the stories that appear on the internet refer to Dr Nissen with names like "St Steven", "Patron Saint of Drug Safety" and "Saint Steven the Pure."
In his email to journalists, Mr Arbesfeld pasted portions of an article which appeared on the Heartwire website, containing umpteen critical comments about Dr Nissen and the Avandia study, as well as comments made by an anonymous blogger on the internet which said that business at the Cleveland Clinic is run similar to a Mafia TV series. The full bog states:
"Wake up pharmaceutical companies, this is a call from Dr. Nissen, if you don't hire the Cleveland Clinic for your big trials then you face the firing squad from Nissen and Company."
"The Cleveland Clinic was one of the most respected names in medicine, now they are positioning themselves as candidates to take over for a new series on HBO to replace the Soprano's — the Clinico's 'next week who should we wack ......' — Bata bing bata boon. Comment by Brian A - May 22, 2007."
However, it could just as easily be inferred that Mr Arbesfeld authored the slanderous blog and supplied it to Heartwire with the intention of quoting it later from a “reputable” web site. For its part, Heartwire has since removed what it says are "unsubstantiated remarks about Dr Nissen and the Cleveland Clinic", and states: "In retrospect we regret that we published those sentences, as they do not meet the highest standards of journalistic or scientific integrity or credibility."
The smear campaign has federal lawmakers up in arms. At a June 6, 2007, hearing before the House Oversight and Government Reform Committee, in response to questions about Mr Arbesfeld sending the e-mail under his official title of FDA spokesman, FDA Commissioner Andrew von Eschenbach told the lawmakers, "It was an inappropriate and unfortunate act on the part of an individual which has been addressed through disciplinary procedures."
Dr Nissen is none to happy about the stunt either. "I'm a pretty tough guy," he told ABC News on May 30, 2007, "but I'll tell you, having this kind of an e-mail that questions my motives, broadcast to the major journalists with whom I work and have established a reputation, is -- it's an outrage."
As for his part, Mr Arbesfeld told the Boston Globe that the email reflected his own personal views and not the FDA's. Any assertion that the email reflected his own personal views is not quite credible considering that his previous employment was always promoting the views of the industry.
A few articles in the media mentioned that Mr Arbesfeld worked for Johnson & Johnson, but his employment with public relations firm Manning Selvage & Lee was not noted. On December 16, 1999, the Healthcare Marketing & Communications Council reported that Mr Arbesfeld had joined Manning as Senior Vice President in New York.
On January 5, 2001, the firm issued a press release to announce the promotion of Mr Arbesfeld and others and referred to Manning as "one of the largest healthcare practices worldwide and has a broad array of clients including Allergan, Amgen, Eli Lilly and Company, Genentech, Hoffmann La-Roche, Kaiser Permanente, Novartis, Pharmacia and Procter & Gamble."
In reading the press release, Mr Arbesfeld's email expertise is apparently a bi-product of his work for Manning. "In this role," it said, "Arbesfeld will help healthcare clients maximize internet-relations in the marketing and communications mix, and will expand the Practice's strategic e-product offerings."
On August 5, 2002, he identified himself in a Reuters article as representing none other than Glaxo, along with six other drug giants including Bristol-Myers, Aventis, J&J, AstraZeneca, Abbott Labs and Novartis, in a campaign to promote the "Together Rx" prescription drug card program for senior citizens. In 2005, the Reporters Handbook listed him as the contact person for J&J subsidiaries, Janssen Pharmaceutica, Ortho-McNeil Pharmaceutical and Ortho Biotech Products.
Less than a week after Mr Arbesfeld's hatchet job on Dr Nissen, ex-FDA Deputy Commissioner Dr Scott Gottlieb planted an editorial in the May 29, 2007, Wall Street Journal entitled, "Journalist Malpractice," accusing the New England Medical Journal of intentionally publishing the Nissen study to make the FDA look impotent. "The publication was timed," he wrote, "to get ahead of the Food and Drug Administration's more careful evaluation of the same issues."
"The journal seemed bent on beating the FDA to the punch," Dr Gottlieb claimed.
"The goal?" he said, "Painting the FDA as impotent, in order to argue for legislation winding through Congress that would increase regulatory hurdles for drug approvals."
The only problem with the Nissen-NEJM conspiracy theory is that the issue under investigation in Congress right now is why the FDA did not warn the public about Avandia heart risks six months before the Nissen study was ever published.
In the end, when it comes to "Journalistic Malpractice," the larger question would seem to be how was it that so many industry shills were able to get the major media outlets and medical journals to immediately publish commentaries and editorials attacking the NEJM and the Nissen research with headlines splashing all over the internet.
In his editorial, Dr Gottlieb notes that there are "questions" whether Avandia is associated with heart risks, but says they are "so far unsupported by more rigorous, randomized studies and extensive review by the FDA and other authorities around the world."
"When it comes to the issue du jour, drug safety," he wrote, "no description of medical research in a medical journal comes close to the detail level or scrutiny imposed by the FDA on study results before approval."
There is no doubt much truth to this assertion, but the problem is that the industry insiders running the FDA refuse to act on the advice of the agency's top scientists. In a July 26, 2007, speech on the Senate floor, Senator Charles Grassley (R-Iowa), of the Senate Finance Committee, said that, in the case of Avandia, "Not only did the FDA disregard the concerns and recommendations from the office responsible for post-marketing surveillance, but I have found that it also attempted to suppress scientific dissent."
In the past two months, he told his fellow senators, "I've had to write to the FDA regarding the suppression of dissent from not one but two FDA officials involved in the review of Avandia."
The Heartwire website conveniently echoed Dr Gottlieb's sentiments by featuring portions of a May 23, 2007, unsigned editorial from the medical journal The Lancet, which claimed that the verdict on Avandia should await the results of a Glaxo sponsored trial called RECORD, not due out until 2009.
"Taken together," the editorial said of Dr Nissen's findings, "these results, although based on very small numbers of events, certainly raise a signal of concern and indicate the need for more reliable information about rosiglitazone's safety."
"But the FDA, physicians, and patients can reasonably await the results of RECORD, a phase 3 trial designed specifically to study cardiovascular outcomes," it said.
"Until the results of RECORD are in," the Lancet noted, "it would be premature to overinterpret a meta-analysis that the authors and NEJM editorialists all acknowledge contains important weaknesses."
The problem with waiting two years for the results of the RECORD trial is that FDA scientist Dr David Graham reviewed the results of this study thus far and told an FDA advisory panel that the study design is so flawed that the results should not be considered in any risk benefit analysis of Avandia now, or in 2009, in a July 26, 2007 report.
In fact, Dr Graham says the RECORD study is so useless that it's probably unethical to allow it to continue because no possible benefit can be achieved by allowing it to go on and that Avandia should be pulled off the market now because thousands of patients are being injured each month by using the drug.
At the end of his editorial, Dr Gottlieb lists himself as a physician and a resident fellow at the American Enterprise Institute who was Deputy Commissioner of the FDA from 2005 to 2007. However, back on August 24, 2005, the Seattle Times provided a much better picture of his background and highlighted the oddity of the FDA hiring him in the first place in light of his solid alliance with the industry. "Only a month ago," the article states, "Dr Scott Gottlieb was a Wall Street insider, promoting hot biotech stocks to investors."
"Now Gottlieb holds the No. 2 job,"” the Times notes, "at the federal agency that approves new drugs, oversees their safety and affects the fortunes of companies he once touted."
"Now, as one of three deputy commissioners," the article said, "Gottlieb will help oversee such major policies as the FDA's fast-track approval process for drug and biotech products, a priority for many Wall Street funds and the pharmaceutical industry."
The Times also noted that a half-dozen current and former FDA officials said they did not know of anyone else from Wall Street ever moving directly into such a high-level job at the agency.
A couple months later, the November 12, 2005, Boston Globe reported that Dr Gottlieb could not participate in formulating the nation's defense plan against the avian flu due to conflicts of interest. He "was recused from key parts of the planning effort because his past consulting work for Manning Selvage & Lee involved companies whose products would be used to combat a flu pandemic," it said.
The article pointed out that Dr Gottlieb's former clients included Roche, the manufacturer of Tamiflu, and Sanofi-Aventis, the parent company of the nation's sole flu vaccine maker.
According to the Globe, Manning paid Gottlieb a $12,500 monthly retainer for nine months for projects that included eight companies, and he was also paid $9,000 for private consulting work for VanGen Inc, a firm that won a $878-million contract to supply the US government with 75 million doses of anthrax vaccine.
In communicating with the FDA, lawmakers have mentioned that they found it "troubling" that Mr Arbesfeld might be trying to settle old scores with Dr Nissen because they were on opposite sides regarding the approval of the heart failure drug Natrecor.
However, Dr Nissen and Dr Gottlieb's disputes go way back as well. In fact, on August 2, 2006, they participated in a debate on the topic: "Government Science Panels: Fair and Balanced?" sponsored by the Center for Science in the Public Interest, and reported on by Russell Mokhiber and Robert Weissman in Common Dreams.
Much to his credit, Dr Nissen openly communicated his objections to the industry's infiltration of the FDA. While sitting right next Dr Gottlieb, he candidly described the conflicts of interest which he stated were "evident at the highest levels of the FDA."
"For years," he said of FDA leadership, "we had an interim FDA Commissioner, Lester Crawford, who shortly after confirmation, abruptly resigns, apparently because he and his wife owned stock in regulated companies."
"Then the administration appointed Andrew von Eschenbach as interim commissioner creating another conflict," he said. "In his role as director of the National Cancer Institute, von Eschenbach must seek FDA approval for human testing or approval of new cancer drugs, an obvious conflict," he noted.
"But even worse," Dr Nissen stated, "the administration appointed Scott Gottlieb as deputy commissioner."
"He came to this job with no regulatory experience, directly from Wall Street, where he served as a biotech analyst and stock promoter," Dr Nissen told the audience.
Dr Gottlieb's response to Dr Nissen's comments was basically that he would not dignify the comments with a response.
Firms that Dr Gottlieb was involved with prior to his gig at the FDA, according to the Globe, also include the Inamed Corp, one of two companies that were seeking to return silicone gel implants to the market and on November 17, 2006, the FDA announced that it would lift restrictions on the sale of the implants.
When Dr Gottlieb left the FDA, he headed right back to greener pastures with the drug giant Novartis. The press release to announce his hiring read: "Bench International Places Eminent Regulatory Advisor Scott Gottlieb, M.D., as Senior Counsel to Novartis."
"Under an exclusive consulting agreement," the release stated, "Scott Gottlieb, M.D., will provide advisory services to Novartis on matters of global regulatory policy and strategy."
The FDA recruited two members of its alumni, Peter Pitts and Robert Goldberg, to take another swipe at Dr Nissen in a June 6, 2007, commentary in the Washington Times, using the same talking points as the anonymous blogger, by referring to Dr Nissen as a "self-appointed and media-anointed Patron Saint of Drug Safety" and "Saint Steven the Pure."
For much of the childish commentary, they poke fun at Dr Nissen because he acknowledged in the NEJM that he consults for many drug companies but said he "requires them to donate all honoraria or consulting fees directly to charity so that he receives neither income nor a tax deduction."
At the end of the commentary, Mr Pitts says he is a former FDA associate commissioner, and both men list their affiliation with the Center for Medicine in the Public Interest; but as usual, that listing really does not give credit where credit is due.
On its web site, the Center describes itself as "a non-partisan, non-profit educational charity," and Mr Pitts is indeed listed as President, but his bio also says he is the Senior Vice President for Global Health Affairs at none other than Manning, Selvege & Lee.
The Manning firm apparently fills two important roles. It's a breeding ground for industry moles preparing to enter "public service" and serves as an employment hub for industry shills once they finish their on average 2- to 3-year stint inside the Bush Administration.
In his CMPI bio, Mr Pitts describes his duties as the FDA's Associate Commissioner from 2002 to 2004 as serving as the agency's "Chief Messaging Officer."
On June 7, 2007, Mr Pitts had this to say in defense of fellow hit-man Mr Arbesfeld on the Pharmalot web site: "I know Doug Arbesfeld and he is a guy devoted to advancing the public health."
According to Mr Pitts, in sending the derogatory e-mail about Dr Nissen to journalists, Mr Arbesfeld was just standing up for the FDA and that people should know about the sacrifice he made by accepting a job in government.
"He is also a guy," Mr Pitts says, "who took a pretty significant pay cut to put in some time in public service."
Some would no doubt argue that it's difficult to imagine that Mr Arbesfeld will end up in the poor house as a result of serving as the top industry mole inside the FDA.
Mr Pitts' sidekick, Mr Goldberg, is indeed listed as the vice president of CMPI, but Mr Goldberg's bio also says he used to be Director of the Manhattan Institute's Center for Medical Progress and Chairman of its 21st Century FDA Task Force.
In fact, a review of the CMPI web site turned up a whole nest of ex-moles who served the industry in one capacity or another in the Bush Administration's FDA. For instance, Daniel Troy, the former FDA Chief Counsel, also known as the "Godfather of Preemption," sits on this "charity's" Advisory Board.
His bio points out that he "played a principal role in FDA’s generally successful assertion of preemption in selected product liability cases."
This "assertion of preemption" says that, as long as the FDA has approved a drug and its label, private citizens in state courts cannot sue the drug company for failing to warn about a product's serious health risks, even in cases where it can be shown that the company concealed studies that revealed the risk from the public and the FDA.
Now that he's switched back to private practice, Mr Troy's CMPI bio says he currently specializes in constitutional and appellate litigation, as well as strategic counseling with "particular focus" on what else - clients regulated by the FDA.
The Advisory Board also includes, Tomas Philipson, whose bio says he served as the Senior Economic Advisor to the commissioner of FDA during 2003 and 2004 and as the Senior Economic Advisor to the administrator of the Centers for Medicare and Medicaid Services in 2004 and 2005.
That would mean that Mr Philipson served Mark McClellan, and they are now apparently joined at the hip because, as part of a program called "Patient-Centric and Prospective Medicine," CMPI says it has created the Patient-Centric Health Forum and that Mr McClellan, "former Medicare administrator and FDA commissioner, will chair the group."
So, it would appear that anyone looking for the retirement home for industry hit men who served in the Bush Administration's FDA can find it right in the middle of cyberspace on the CMPI web site.
(This article is part of the Avandia Update series sponsored by the Baum Hedlund law firm)
The FDA's latest campaign to protect the profits of a drug company over the safety of Americans is unprecedented, and the organizers include a gang of current and former FDA officials largely credited with turning the nation's regulatory beagle into a lapdog for Big Pharma under the Bush Administration.
FDA spokesman Douglas Arbesfeld, apparently the industry's new inside guy, kicked off the campaign by sending an e-mail to journalists which was intended to discredit Dr Steven Nissen and the Cleveland Clinic. Dr Nissen's study appeared online on May 21, 2007, in the New England Journal of Medicine and warned that GlaxoSmithKline's diabetes drug Avandia increased the risk of heart attacks by 43% and death from cardiovascular events by possibly 64%.
The talking points for the media were obviously agreed upon ahead of time because the stories that appear on the internet refer to Dr Nissen with names like "St Steven", "Patron Saint of Drug Safety" and "Saint Steven the Pure."
In his email to journalists, Mr Arbesfeld pasted portions of an article which appeared on the Heartwire website, containing umpteen critical comments about Dr Nissen and the Avandia study, as well as comments made by an anonymous blogger on the internet which said that business at the Cleveland Clinic is run similar to a Mafia TV series. The full bog states:
"Wake up pharmaceutical companies, this is a call from Dr. Nissen, if you don't hire the Cleveland Clinic for your big trials then you face the firing squad from Nissen and Company."
"The Cleveland Clinic was one of the most respected names in medicine, now they are positioning themselves as candidates to take over for a new series on HBO to replace the Soprano's — the Clinico's 'next week who should we wack ......' — Bata bing bata boon. Comment by Brian A - May 22, 2007."
However, it could just as easily be inferred that Mr Arbesfeld authored the slanderous blog and supplied it to Heartwire with the intention of quoting it later from a “reputable” web site. For its part, Heartwire has since removed what it says are "unsubstantiated remarks about Dr Nissen and the Cleveland Clinic", and states: "In retrospect we regret that we published those sentences, as they do not meet the highest standards of journalistic or scientific integrity or credibility."
The smear campaign has federal lawmakers up in arms. At a June 6, 2007, hearing before the House Oversight and Government Reform Committee, in response to questions about Mr Arbesfeld sending the e-mail under his official title of FDA spokesman, FDA Commissioner Andrew von Eschenbach told the lawmakers, "It was an inappropriate and unfortunate act on the part of an individual which has been addressed through disciplinary procedures."
Dr Nissen is none to happy about the stunt either. "I'm a pretty tough guy," he told ABC News on May 30, 2007, "but I'll tell you, having this kind of an e-mail that questions my motives, broadcast to the major journalists with whom I work and have established a reputation, is -- it's an outrage."
As for his part, Mr Arbesfeld told the Boston Globe that the email reflected his own personal views and not the FDA's. Any assertion that the email reflected his own personal views is not quite credible considering that his previous employment was always promoting the views of the industry.
A few articles in the media mentioned that Mr Arbesfeld worked for Johnson & Johnson, but his employment with public relations firm Manning Selvage & Lee was not noted. On December 16, 1999, the Healthcare Marketing & Communications Council reported that Mr Arbesfeld had joined Manning as Senior Vice President in New York.
On January 5, 2001, the firm issued a press release to announce the promotion of Mr Arbesfeld and others and referred to Manning as "one of the largest healthcare practices worldwide and has a broad array of clients including Allergan, Amgen, Eli Lilly and Company, Genentech, Hoffmann La-Roche, Kaiser Permanente, Novartis, Pharmacia and Procter & Gamble."
In reading the press release, Mr Arbesfeld's email expertise is apparently a bi-product of his work for Manning. "In this role," it said, "Arbesfeld will help healthcare clients maximize internet-relations in the marketing and communications mix, and will expand the Practice's strategic e-product offerings."
On August 5, 2002, he identified himself in a Reuters article as representing none other than Glaxo, along with six other drug giants including Bristol-Myers, Aventis, J&J, AstraZeneca, Abbott Labs and Novartis, in a campaign to promote the "Together Rx" prescription drug card program for senior citizens. In 2005, the Reporters Handbook listed him as the contact person for J&J subsidiaries, Janssen Pharmaceutica, Ortho-McNeil Pharmaceutical and Ortho Biotech Products.
Less than a week after Mr Arbesfeld's hatchet job on Dr Nissen, ex-FDA Deputy Commissioner Dr Scott Gottlieb planted an editorial in the May 29, 2007, Wall Street Journal entitled, "Journalist Malpractice," accusing the New England Medical Journal of intentionally publishing the Nissen study to make the FDA look impotent. "The publication was timed," he wrote, "to get ahead of the Food and Drug Administration's more careful evaluation of the same issues."
"The journal seemed bent on beating the FDA to the punch," Dr Gottlieb claimed.
"The goal?" he said, "Painting the FDA as impotent, in order to argue for legislation winding through Congress that would increase regulatory hurdles for drug approvals."
The only problem with the Nissen-NEJM conspiracy theory is that the issue under investigation in Congress right now is why the FDA did not warn the public about Avandia heart risks six months before the Nissen study was ever published.
In the end, when it comes to "Journalistic Malpractice," the larger question would seem to be how was it that so many industry shills were able to get the major media outlets and medical journals to immediately publish commentaries and editorials attacking the NEJM and the Nissen research with headlines splashing all over the internet.
In his editorial, Dr Gottlieb notes that there are "questions" whether Avandia is associated with heart risks, but says they are "so far unsupported by more rigorous, randomized studies and extensive review by the FDA and other authorities around the world."
"When it comes to the issue du jour, drug safety," he wrote, "no description of medical research in a medical journal comes close to the detail level or scrutiny imposed by the FDA on study results before approval."
There is no doubt much truth to this assertion, but the problem is that the industry insiders running the FDA refuse to act on the advice of the agency's top scientists. In a July 26, 2007, speech on the Senate floor, Senator Charles Grassley (R-Iowa), of the Senate Finance Committee, said that, in the case of Avandia, "Not only did the FDA disregard the concerns and recommendations from the office responsible for post-marketing surveillance, but I have found that it also attempted to suppress scientific dissent."
In the past two months, he told his fellow senators, "I've had to write to the FDA regarding the suppression of dissent from not one but two FDA officials involved in the review of Avandia."
The Heartwire website conveniently echoed Dr Gottlieb's sentiments by featuring portions of a May 23, 2007, unsigned editorial from the medical journal The Lancet, which claimed that the verdict on Avandia should await the results of a Glaxo sponsored trial called RECORD, not due out until 2009.
"Taken together," the editorial said of Dr Nissen's findings, "these results, although based on very small numbers of events, certainly raise a signal of concern and indicate the need for more reliable information about rosiglitazone's safety."
"But the FDA, physicians, and patients can reasonably await the results of RECORD, a phase 3 trial designed specifically to study cardiovascular outcomes," it said.
"Until the results of RECORD are in," the Lancet noted, "it would be premature to overinterpret a meta-analysis that the authors and NEJM editorialists all acknowledge contains important weaknesses."
The problem with waiting two years for the results of the RECORD trial is that FDA scientist Dr David Graham reviewed the results of this study thus far and told an FDA advisory panel that the study design is so flawed that the results should not be considered in any risk benefit analysis of Avandia now, or in 2009, in a July 26, 2007 report.
In fact, Dr Graham says the RECORD study is so useless that it's probably unethical to allow it to continue because no possible benefit can be achieved by allowing it to go on and that Avandia should be pulled off the market now because thousands of patients are being injured each month by using the drug.
At the end of his editorial, Dr Gottlieb lists himself as a physician and a resident fellow at the American Enterprise Institute who was Deputy Commissioner of the FDA from 2005 to 2007. However, back on August 24, 2005, the Seattle Times provided a much better picture of his background and highlighted the oddity of the FDA hiring him in the first place in light of his solid alliance with the industry. "Only a month ago," the article states, "Dr Scott Gottlieb was a Wall Street insider, promoting hot biotech stocks to investors."
"Now Gottlieb holds the No. 2 job,"” the Times notes, "at the federal agency that approves new drugs, oversees their safety and affects the fortunes of companies he once touted."
"Now, as one of three deputy commissioners," the article said, "Gottlieb will help oversee such major policies as the FDA's fast-track approval process for drug and biotech products, a priority for many Wall Street funds and the pharmaceutical industry."
The Times also noted that a half-dozen current and former FDA officials said they did not know of anyone else from Wall Street ever moving directly into such a high-level job at the agency.
A couple months later, the November 12, 2005, Boston Globe reported that Dr Gottlieb could not participate in formulating the nation's defense plan against the avian flu due to conflicts of interest. He "was recused from key parts of the planning effort because his past consulting work for Manning Selvage & Lee involved companies whose products would be used to combat a flu pandemic," it said.
The article pointed out that Dr Gottlieb's former clients included Roche, the manufacturer of Tamiflu, and Sanofi-Aventis, the parent company of the nation's sole flu vaccine maker.
According to the Globe, Manning paid Gottlieb a $12,500 monthly retainer for nine months for projects that included eight companies, and he was also paid $9,000 for private consulting work for VanGen Inc, a firm that won a $878-million contract to supply the US government with 75 million doses of anthrax vaccine.
In communicating with the FDA, lawmakers have mentioned that they found it "troubling" that Mr Arbesfeld might be trying to settle old scores with Dr Nissen because they were on opposite sides regarding the approval of the heart failure drug Natrecor.
However, Dr Nissen and Dr Gottlieb's disputes go way back as well. In fact, on August 2, 2006, they participated in a debate on the topic: "Government Science Panels: Fair and Balanced?" sponsored by the Center for Science in the Public Interest, and reported on by Russell Mokhiber and Robert Weissman in Common Dreams.
Much to his credit, Dr Nissen openly communicated his objections to the industry's infiltration of the FDA. While sitting right next Dr Gottlieb, he candidly described the conflicts of interest which he stated were "evident at the highest levels of the FDA."
"For years," he said of FDA leadership, "we had an interim FDA Commissioner, Lester Crawford, who shortly after confirmation, abruptly resigns, apparently because he and his wife owned stock in regulated companies."
"Then the administration appointed Andrew von Eschenbach as interim commissioner creating another conflict," he said. "In his role as director of the National Cancer Institute, von Eschenbach must seek FDA approval for human testing or approval of new cancer drugs, an obvious conflict," he noted.
"But even worse," Dr Nissen stated, "the administration appointed Scott Gottlieb as deputy commissioner."
"He came to this job with no regulatory experience, directly from Wall Street, where he served as a biotech analyst and stock promoter," Dr Nissen told the audience.
Dr Gottlieb's response to Dr Nissen's comments was basically that he would not dignify the comments with a response.
Firms that Dr Gottlieb was involved with prior to his gig at the FDA, according to the Globe, also include the Inamed Corp, one of two companies that were seeking to return silicone gel implants to the market and on November 17, 2006, the FDA announced that it would lift restrictions on the sale of the implants.
When Dr Gottlieb left the FDA, he headed right back to greener pastures with the drug giant Novartis. The press release to announce his hiring read: "Bench International Places Eminent Regulatory Advisor Scott Gottlieb, M.D., as Senior Counsel to Novartis."
"Under an exclusive consulting agreement," the release stated, "Scott Gottlieb, M.D., will provide advisory services to Novartis on matters of global regulatory policy and strategy."
The FDA recruited two members of its alumni, Peter Pitts and Robert Goldberg, to take another swipe at Dr Nissen in a June 6, 2007, commentary in the Washington Times, using the same talking points as the anonymous blogger, by referring to Dr Nissen as a "self-appointed and media-anointed Patron Saint of Drug Safety" and "Saint Steven the Pure."
For much of the childish commentary, they poke fun at Dr Nissen because he acknowledged in the NEJM that he consults for many drug companies but said he "requires them to donate all honoraria or consulting fees directly to charity so that he receives neither income nor a tax deduction."
At the end of the commentary, Mr Pitts says he is a former FDA associate commissioner, and both men list their affiliation with the Center for Medicine in the Public Interest; but as usual, that listing really does not give credit where credit is due.
On its web site, the Center describes itself as "a non-partisan, non-profit educational charity," and Mr Pitts is indeed listed as President, but his bio also says he is the Senior Vice President for Global Health Affairs at none other than Manning, Selvege & Lee.
The Manning firm apparently fills two important roles. It's a breeding ground for industry moles preparing to enter "public service" and serves as an employment hub for industry shills once they finish their on average 2- to 3-year stint inside the Bush Administration.
In his CMPI bio, Mr Pitts describes his duties as the FDA's Associate Commissioner from 2002 to 2004 as serving as the agency's "Chief Messaging Officer."
On June 7, 2007, Mr Pitts had this to say in defense of fellow hit-man Mr Arbesfeld on the Pharmalot web site: "I know Doug Arbesfeld and he is a guy devoted to advancing the public health."
According to Mr Pitts, in sending the derogatory e-mail about Dr Nissen to journalists, Mr Arbesfeld was just standing up for the FDA and that people should know about the sacrifice he made by accepting a job in government.
"He is also a guy," Mr Pitts says, "who took a pretty significant pay cut to put in some time in public service."
Some would no doubt argue that it's difficult to imagine that Mr Arbesfeld will end up in the poor house as a result of serving as the top industry mole inside the FDA.
Mr Pitts' sidekick, Mr Goldberg, is indeed listed as the vice president of CMPI, but Mr Goldberg's bio also says he used to be Director of the Manhattan Institute's Center for Medical Progress and Chairman of its 21st Century FDA Task Force.
In fact, a review of the CMPI web site turned up a whole nest of ex-moles who served the industry in one capacity or another in the Bush Administration's FDA. For instance, Daniel Troy, the former FDA Chief Counsel, also known as the "Godfather of Preemption," sits on this "charity's" Advisory Board.
His bio points out that he "played a principal role in FDA’s generally successful assertion of preemption in selected product liability cases."
This "assertion of preemption" says that, as long as the FDA has approved a drug and its label, private citizens in state courts cannot sue the drug company for failing to warn about a product's serious health risks, even in cases where it can be shown that the company concealed studies that revealed the risk from the public and the FDA.
Now that he's switched back to private practice, Mr Troy's CMPI bio says he currently specializes in constitutional and appellate litigation, as well as strategic counseling with "particular focus" on what else - clients regulated by the FDA.
The Advisory Board also includes, Tomas Philipson, whose bio says he served as the Senior Economic Advisor to the commissioner of FDA during 2003 and 2004 and as the Senior Economic Advisor to the administrator of the Centers for Medicare and Medicaid Services in 2004 and 2005.
That would mean that Mr Philipson served Mark McClellan, and they are now apparently joined at the hip because, as part of a program called "Patient-Centric and Prospective Medicine," CMPI says it has created the Patient-Centric Health Forum and that Mr McClellan, "former Medicare administrator and FDA commissioner, will chair the group."
So, it would appear that anyone looking for the retirement home for industry hit men who served in the Bush Administration's FDA can find it right in the middle of cyberspace on the CMPI web site.
(This article is part of the Avandia Update series sponsored by the Baum Hedlund law firm)
Shelhigh and FDA play Blame Game Over Sale of Contaminated Devices
Evelyn Pringle May 15, 2007
On April 17, 2007, the FDA issued a press release to announce that US Marshals had seized all implantable medical devices from Shelhigh, Inc, in Union, NJ, after finding "significant deficiencies in the company's manufacturing processes."
"The deficiencies," the agency said, "may compromise the safety and effectiveness of the products, particularly their sterility."
According to the FDA, if not sterile, the use of these devices poses a reasonable probability of serious adverse events or death.
But critics say the real story here involves the FDA's knowledge about the safety hazards at Shelhigh dating back to at least 2000, and the fact that it allowed patients to be implanted with the firm's devices for basically 7 years.
In the press release, the FDA says it inspected the Shelhigh facility last fall, and warned the firm in a meeting that failure to correct the violations could result in an enforcement action. The agency also noted that it had sent two previous warning letters to the firm about manufacturing deficiencies and other violations.
However, on its web site, Shelhigh has posted a response to the public statements made by the FDA and squarely points the finger of blame at the agency for allowing the sale of the potentially contaminated devices to continue.
"If the FDA truly believes what it claimed," Shelhigh states, "then the FDA is negligent and guilty of professional misconduct for permitting the use of Shelhigh products during the 10 weeks when 2-3 FDA inspectors were present at the Shelhigh facility and for 4 months afterwards."
But the history of the controversy at the center of this blame game goes back a lot further than last fall. According to the complaint filed in US District Court of New Jersey by the US Attorney for the District of New Jersey, to support the seizure of Shelhigh's products, the first FDA warning letter referred to in the agency's press release was sent 7 years ago on April 26, 2000, and the second warning letter was sent December 14, 2005.
In assessing blame, its necessary to understanding that FDA regulations require device makers to have systems in place to accept and analyze all complaints received from doctors and hospitals and to forward all complaints that indicate that a device failure may have contributed to the injury or death of a patient to the FDA.
The first warning letter proves that on April 26, 2000, the FDA was aware that patients who were implanted with Shelhigh devices were developing serious infections that required surgery to remove the devices and that Shelhigh refused to investigate the adverse events to determine whether its products were contaminated.
In the letter, the FDA said, Shelhigh "failed to evaluate" complaints of patients who developed infections which required surgical removal of the implant to determine whether the infection was due to the malfunction of the device.
The agency also pointed out that despite the fact that there were 4 separate event reports filed with Medwatch from one source that involved patients with infections so severe that the device had to be explanted, there "was no written evaluation or investigation of these Medwatch complaints," by Shelhigh.
The letter also stated that there were 43 problems related to infections of implanted devices reported by the firm's distributor, Classic Medical on October 14, 1999, which "were not recorded and evaluated as product complaints."
Jumping ahead to the FDA's latest list of safety violations, they include Shelhigh's failure to (1) adequately monitor critical manufacturing environments for possible microbial contamination; (2) properly test products for sterility and fever-causing contaminants; (3) scientifically support product expiration dates; and (4) manufacturing products in a poorly constructed and maintained clean room where sterilized devices are further processed.
On April 18, 2007, the FDA sent out a Dear Healthcare Provider letter stating, "This is to notify you that all medical devices manufactured by Shelhigh ... were manufactured under conditions that may have contaminated the devices and may result in devices that fail to function for the expected life of the products."
The FDA also said, it was aware of published reports of premature or accelerated failure associated with some devices and the products could potentially be contaminated with bacteria, fungi, and endotoxin. The letter recommended that providers assess the overall health status of each patient, and provide the testing, monitoring and care appropriate to each patient's individual case.
On April 19, 2007, the FDA issued a public advisory for patients stating: "Devices manufactured by Shelhigh, Inc. may have been implanted during various surgical procedures, including open-heart surgery for valve replacement; and repair of soft tissue structures during abdominal, pelvic, heart, lung, brain, shoulder, and spine surgery."
The advisory warns that patients vulnerable to infection and those at high risk for complications include the critically ill, children, the elderly, and pregnant women.
Noting that the devices have been available since 1997, the FDA tells patients, "The number of these devices that may be contaminated or experience problems isn't known at this time," and problems "could occur at anytime, and may become apparent to you and your physician during routine examination."
According to the agency, the seizure last month involves many products and includes pediatric heart valves and conduits, described as "tube-like devices for blood flow," surgical patches, arterial grafts, dural patches, which aid in tissue recovery after neurosurgery, and annuloplasty rings, used to help repair heart valves.
The FDA may not know how many devices have been sold but in the May 3, 2007, Star-Ledger, Shelhigh's marketing director, Douglas Goldman reported that, "thousands and thousands of the company's implants have been used since Shelhigh began distributing products 10 years ago."
The FDA's warning to patients amounts to a life-sentence of worry and medical care because the devices are permanently implanted into infants, children and adults and the agency advises doctors to monitor patients for infections and proper device functioning throughout "the expected lifetime of the device."
The meeting referred to in the FDA press release took place almost a year ago on June 16, 2006, and according the complaint filed with the court, "the firm was again warned by FDA that continuation of the violative conduct could result in seizure, injunction, and/or civil money penalties."
The inspections referred to in the press release took place between October 11 - December 20, 2006, and "revealed that the methods used in, and the facilities and controls used for, the manufacture, design, packing, storage, and installation of the devices do not comply" with safety regulations, according to the complaint.
"Because the firm's devices are implanted into patients," it states, "ensuring continued sterility is critical."
However, ensuring sterility was apparently not a priority to the FDA being it permitted the hazardous devices to be implanted for 7 years. The complaint was not filed until April 16, 2007, and in it, the FDA now claims, "the firm allowed at least four lots of devices that failed sterility testing to be released for distribution in the last two years."
This is certainly a bizarre allegation considering that the FDA allowed the sale of the devices in the same two years. On April 24, 2007, the arrogant founder of the Shilhigh, Shlomo Gabbay, MD, blasted the FDA on this point in a press release stating:
"There is absolutely no FDA recall of our devices which the FDA claims may cause patient injury. If our products were truly questionable as the FDA is leading the Public to believe, the FDA could have requested a remedy at any time - why haven't they?"
Legal experts are not amused by the public spectacle of the firm and the FDA arguing over who's to blame for knowingly implanting patients with potentially contaminated devices.
Attorney, Derek Braslow, of the Pennsylvania Law Firm, Pogust & Braslow, has plenty of experience fighting for the "little guy" against the giant drug companies in large part because of the fact that the industry friendly FDA, under the Bush Administration, refuses to protect the public from dangerous products placed on the market by an industry comprised of the most generous Bush campaign contributors.
In this instance, Attorney Braslow says the conduct of both Shelhigh and the FDA is "outrageous."
"This is another example of a pharmaceutical company placing profits over people and further," he says, "why we cannot continue to rely on the FDA to protect Americans from dangerous drugs and devices."
"Instead of feigning worry about Americans importing contaminated drugs from Canada," he notes, "our government should be more concerned about the contaminated products in its own backyard."
"I doubt that even the Senate's proposed new drug safety legislation will end up being strong enough to prevent this kind of outrageous conduct," he warns.
"As far as I'm concerned," he says, "the FDA's action is too little, too late."
But Mr Braslow also says, "the failure of the FDA does not give this company a free pass."
"Shelhigh must be held responsible for its criminal conduct," he points out, "not only by the government but by those patients it injured."
According to the FDA, at the time of the seizure, Shelhigh was asked several times to voluntarily recall all of the products that remained on the market but declined to do so. On May 2, 2007, the FDA sent a letter to Shelhigh formally requesting the recall of all devices including those in hospital inventories.
On May 3, 2007, Mr Gabbay issued his own press release and callously refused to recall the devices to prevent the possibility of more implant victims. "This is the first formal request by the FDA for Shelhigh to recall its products," he said, "and since the FDA allegations are unfounded, Shelhigh has no intention to initiate a product recall."
"The FDA," he said, "should understand that it must prove its allegations before it can make a request and their newest statements do not provide any further factual support for their claims."
Mr Gabbay and the FDA can argue over blame until the cows come home but the cold hard truth is that nobody will ever know how many serious injuries and deaths have occurred over the past 7 years that were not rightly attributed to the company's contaminated devices and the FDA's failure once again to protect the public.
On April 17, 2007, the FDA issued a press release to announce that US Marshals had seized all implantable medical devices from Shelhigh, Inc, in Union, NJ, after finding "significant deficiencies in the company's manufacturing processes."
"The deficiencies," the agency said, "may compromise the safety and effectiveness of the products, particularly their sterility."
According to the FDA, if not sterile, the use of these devices poses a reasonable probability of serious adverse events or death.
But critics say the real story here involves the FDA's knowledge about the safety hazards at Shelhigh dating back to at least 2000, and the fact that it allowed patients to be implanted with the firm's devices for basically 7 years.
In the press release, the FDA says it inspected the Shelhigh facility last fall, and warned the firm in a meeting that failure to correct the violations could result in an enforcement action. The agency also noted that it had sent two previous warning letters to the firm about manufacturing deficiencies and other violations.
However, on its web site, Shelhigh has posted a response to the public statements made by the FDA and squarely points the finger of blame at the agency for allowing the sale of the potentially contaminated devices to continue.
"If the FDA truly believes what it claimed," Shelhigh states, "then the FDA is negligent and guilty of professional misconduct for permitting the use of Shelhigh products during the 10 weeks when 2-3 FDA inspectors were present at the Shelhigh facility and for 4 months afterwards."
But the history of the controversy at the center of this blame game goes back a lot further than last fall. According to the complaint filed in US District Court of New Jersey by the US Attorney for the District of New Jersey, to support the seizure of Shelhigh's products, the first FDA warning letter referred to in the agency's press release was sent 7 years ago on April 26, 2000, and the second warning letter was sent December 14, 2005.
In assessing blame, its necessary to understanding that FDA regulations require device makers to have systems in place to accept and analyze all complaints received from doctors and hospitals and to forward all complaints that indicate that a device failure may have contributed to the injury or death of a patient to the FDA.
The first warning letter proves that on April 26, 2000, the FDA was aware that patients who were implanted with Shelhigh devices were developing serious infections that required surgery to remove the devices and that Shelhigh refused to investigate the adverse events to determine whether its products were contaminated.
In the letter, the FDA said, Shelhigh "failed to evaluate" complaints of patients who developed infections which required surgical removal of the implant to determine whether the infection was due to the malfunction of the device.
The agency also pointed out that despite the fact that there were 4 separate event reports filed with Medwatch from one source that involved patients with infections so severe that the device had to be explanted, there "was no written evaluation or investigation of these Medwatch complaints," by Shelhigh.
The letter also stated that there were 43 problems related to infections of implanted devices reported by the firm's distributor, Classic Medical on October 14, 1999, which "were not recorded and evaluated as product complaints."
Jumping ahead to the FDA's latest list of safety violations, they include Shelhigh's failure to (1) adequately monitor critical manufacturing environments for possible microbial contamination; (2) properly test products for sterility and fever-causing contaminants; (3) scientifically support product expiration dates; and (4) manufacturing products in a poorly constructed and maintained clean room where sterilized devices are further processed.
On April 18, 2007, the FDA sent out a Dear Healthcare Provider letter stating, "This is to notify you that all medical devices manufactured by Shelhigh ... were manufactured under conditions that may have contaminated the devices and may result in devices that fail to function for the expected life of the products."
The FDA also said, it was aware of published reports of premature or accelerated failure associated with some devices and the products could potentially be contaminated with bacteria, fungi, and endotoxin. The letter recommended that providers assess the overall health status of each patient, and provide the testing, monitoring and care appropriate to each patient's individual case.
On April 19, 2007, the FDA issued a public advisory for patients stating: "Devices manufactured by Shelhigh, Inc. may have been implanted during various surgical procedures, including open-heart surgery for valve replacement; and repair of soft tissue structures during abdominal, pelvic, heart, lung, brain, shoulder, and spine surgery."
The advisory warns that patients vulnerable to infection and those at high risk for complications include the critically ill, children, the elderly, and pregnant women.
Noting that the devices have been available since 1997, the FDA tells patients, "The number of these devices that may be contaminated or experience problems isn't known at this time," and problems "could occur at anytime, and may become apparent to you and your physician during routine examination."
According to the agency, the seizure last month involves many products and includes pediatric heart valves and conduits, described as "tube-like devices for blood flow," surgical patches, arterial grafts, dural patches, which aid in tissue recovery after neurosurgery, and annuloplasty rings, used to help repair heart valves.
The FDA may not know how many devices have been sold but in the May 3, 2007, Star-Ledger, Shelhigh's marketing director, Douglas Goldman reported that, "thousands and thousands of the company's implants have been used since Shelhigh began distributing products 10 years ago."
The FDA's warning to patients amounts to a life-sentence of worry and medical care because the devices are permanently implanted into infants, children and adults and the agency advises doctors to monitor patients for infections and proper device functioning throughout "the expected lifetime of the device."
The meeting referred to in the FDA press release took place almost a year ago on June 16, 2006, and according the complaint filed with the court, "the firm was again warned by FDA that continuation of the violative conduct could result in seizure, injunction, and/or civil money penalties."
The inspections referred to in the press release took place between October 11 - December 20, 2006, and "revealed that the methods used in, and the facilities and controls used for, the manufacture, design, packing, storage, and installation of the devices do not comply" with safety regulations, according to the complaint.
"Because the firm's devices are implanted into patients," it states, "ensuring continued sterility is critical."
However, ensuring sterility was apparently not a priority to the FDA being it permitted the hazardous devices to be implanted for 7 years. The complaint was not filed until April 16, 2007, and in it, the FDA now claims, "the firm allowed at least four lots of devices that failed sterility testing to be released for distribution in the last two years."
This is certainly a bizarre allegation considering that the FDA allowed the sale of the devices in the same two years. On April 24, 2007, the arrogant founder of the Shilhigh, Shlomo Gabbay, MD, blasted the FDA on this point in a press release stating:
"There is absolutely no FDA recall of our devices which the FDA claims may cause patient injury. If our products were truly questionable as the FDA is leading the Public to believe, the FDA could have requested a remedy at any time - why haven't they?"
Legal experts are not amused by the public spectacle of the firm and the FDA arguing over who's to blame for knowingly implanting patients with potentially contaminated devices.
Attorney, Derek Braslow, of the Pennsylvania Law Firm, Pogust & Braslow, has plenty of experience fighting for the "little guy" against the giant drug companies in large part because of the fact that the industry friendly FDA, under the Bush Administration, refuses to protect the public from dangerous products placed on the market by an industry comprised of the most generous Bush campaign contributors.
In this instance, Attorney Braslow says the conduct of both Shelhigh and the FDA is "outrageous."
"This is another example of a pharmaceutical company placing profits over people and further," he says, "why we cannot continue to rely on the FDA to protect Americans from dangerous drugs and devices."
"Instead of feigning worry about Americans importing contaminated drugs from Canada," he notes, "our government should be more concerned about the contaminated products in its own backyard."
"I doubt that even the Senate's proposed new drug safety legislation will end up being strong enough to prevent this kind of outrageous conduct," he warns.
"As far as I'm concerned," he says, "the FDA's action is too little, too late."
But Mr Braslow also says, "the failure of the FDA does not give this company a free pass."
"Shelhigh must be held responsible for its criminal conduct," he points out, "not only by the government but by those patients it injured."
According to the FDA, at the time of the seizure, Shelhigh was asked several times to voluntarily recall all of the products that remained on the market but declined to do so. On May 2, 2007, the FDA sent a letter to Shelhigh formally requesting the recall of all devices including those in hospital inventories.
On May 3, 2007, Mr Gabbay issued his own press release and callously refused to recall the devices to prevent the possibility of more implant victims. "This is the first formal request by the FDA for Shelhigh to recall its products," he said, "and since the FDA allegations are unfounded, Shelhigh has no intention to initiate a product recall."
"The FDA," he said, "should understand that it must prove its allegations before it can make a request and their newest statements do not provide any further factual support for their claims."
Mr Gabbay and the FDA can argue over blame until the cows come home but the cold hard truth is that nobody will ever know how many serious injuries and deaths have occurred over the past 7 years that were not rightly attributed to the company's contaminated devices and the FDA's failure once again to protect the public.
Lilly's Worst Zyprexa Nightmare Comes True
Evelyn Pringle May 7, 2007
Eli Lilly is not all that worried about personal injury lawsuits related to Zyprexa because the company has enough money to pay the relatively small pay-outs that arise from such actions, according to Attorney Barry Turner, a professor of law and ethics in the UK and a leading authority on consumer fraud litigation involving the pharmaceutical industry.
But he says the Medicaid fraud lawsuits filed by 9 states thus far, under the Federal and State False Claims Act are another matter. "The biggest penalties so far in Federal and State False Claims Act violations," Mr Turner reports, "were awarded against drug companies and there are very many more cases under seal."
But an even larger nightmare for top Lilly officials, he says, arises when a product like Zyprexa causes deaths and injuries to consumers and shareholders face huge losses including the millions of people who have their pensions invested in the company.
When a blockbuster drug is announced, Mr Turner says, it attracts huge investment and if that investment has been attracted to a product that Lilly knew was faulty, the company has risked shareholder funds beyond the pale.
This kind of behavior, he notes, is a Sarbox violation. The Sarbanes-Oxley Act was enacted to restore investor confidence in publicly traded companies in the wake of Enron and similar debacles by improving corporate accountability. Its official title is the "Public Company Accounting Reform and Investor Protection Act of 2002," named after its sponsors Senator Paul Sarbanes (D-MD) and Representative Michael G Oxley (R-OH), and is commonly referred to as SOX.
One of the features of SOX is the ability to bring an action against those who recklessly and fraudulently deal with stockholder's money and, "promoting the off label use of a drug with undeclared dangerous side effects, or being negligent as to such promotion, is the kind of behavior justifying an action under Sarbanes Oxley," according to Mr Turner.
"Those at the top of Eli Lilly," he states, "gambled with the lives of patients and the money of stockholders in equal bad faith when they engaged in fraudulent and dishonest behavior that allowed a dangerous drug to be marketed."
"The lifeblood of a business," he says, "is the investment that goes into it and in the case of Eli Lilly it means the investment of millions of shareholders."
"Anyone who defrauds them," he explains, "is defrauding people not business."
Mr Tuner says it is easy to think of shareholders as "rich lazy fat cats" living off the efforts of others but it is fundamentally wrong by ethical standards to think that if they are defrauded that perhaps they deserve it. "What needs to be understood," he says, "is that many millions of people who own no stock at all get defrauded in scams all the time."
"Those who pay into pension funds," he explains, "are vulnerable to the financial shenanigans not only of fund managers but of boards of companies and CEO's that fail to police the companies activities or in some cases actively encourage fraud and reckless business practices."
The worst of all legal nightmares resulting from the Zyprexa "shenanigans," occurred over a period of 9 days between April 2, 2007 and April 11, 2007, when not one, but 4 shareholder class action lawsuits were announced against Lilly and "certain of its officers and directors" filed in the US District Court for the Eastern District of New York, for violations of the Securities and Exchange Act alleging that the defendants hid the side effects of Zyprexa and engaged in illegal off-label marketing campaigns.
On April 2, 2007, the Law Firm of Schiffrin Barroway Topaz & Kessler, issued a press release to announce that a class action was filed on behalf of all securities purchasers of Lilly from March 28, 2002 and December 22, 2006, charging the defendants with disseminating false and misleading statements regarding Zyprexa.
More specifically, it alleges that they were aware of a "clear link" between Zyprexa and diabetes; and yet failed to warn the public and engaged in an illicit scheme to offset a drop in sales that was certain to occur, and did occur, when reports of Zyprexa's side effects emerged, by creating a marketing plan which included the evaluation and pursuit of sales for the drug based on "off-label" uses and that the off-label marketing program was a direct violation of Lilly's own code of conduct.
The complaint further alleges that concealing the side effects and engaging in a massive illegal marketing campaign potentially subjected Lilly to substantial regulatory fines, penalties and other legal action, compromising the company's overall financial condition and prospects.
The complaint reports that between 2002 and 2004, sales of Zyprexa grew from $3.69 billion to $4.42 billion, and that between July 18, 2002 and May 7, 2004, Lilly's stock value increased from $43.75 per share to $76.95.
Throughout the class period, the lawsuit says, Lilly had information about the link between Zyprexa and extreme weight gain and diabetes and in the face of mounting research linking the drug to diabetes and weight gain, and the lawsuits filed by persons who developed these conditions, "Lilly emphatically denied any such link."
The complaint alleges that when public warnings were issued about the safety of Zyprexa, sales slowed and between May 7, 2004 and October 25, 2004, stock prices dropped from $76.95 per share to $50.34, representing a loss of market capitalization of over $30 billion.
The press release cites reports in the New York Times between December 17 and 21, 2006, as disclosing for the "first time" that Lilly had engaged in a decade-long effort to play down the risks of Zyprexa; and actively marketed the drug for illegal off-label uses such as treating elderly patients with symptoms of dementia.
Therefore, the lawsuits alleges, the over $30 billion decline in stock value between May 7, 2004 and October 25, 2004 was the direct result of defendants' fraudulent conduct.
In addition it says, the publication of the Times articles caused another $3.49, or 6.4%, decline in stock value and represented a further market loss of approximately $3.5 billion.
Two days after the first class action was announced, on April 5th, the Lerach Coughlin Stoia Geller Rudman & Robbins Law Firm announced that another had been filed.
The second complaint also charges Lilly and certain of its officers and directors with violations of the Securities Exchange Act, and alleges that at the beginning of the class period, defendants contended that Zyprexa did not cause diabetes-related side effects and that once the clinical data rendered that position untenable, defendants argued instead that Zyprexa did not cause any more side effects than its competitors.
Eventually, the press release notes, more and more clinical data showed that, in fact, Zyprexa does cause such side effects and to a greater extent than its competitors and the "revelations sharply curtailed the sales growth of Zyprexa and resulted in thousands of product liability lawsuits against Lilly and hundreds of millions of dollars in settlements."
It also alleges that defendants intentionally suppressed and misrepresented data showing that Zyprexa causes weight gain, high blood sugar, and diabetes, citing the series of articles in the Times, with excerpted "documents detailing defendants' deception."
The release says the documents revealed that defendants intentionally misled patients, doctors, and investors and as a result, "the price of Lilly's stock declined almost 6% in the five trading days during which the series of articles was published."
The members of the class, it notes, invested in Lilly securities unaware that defendants' fraud had artificially inflated the prices of those securities and when "the truth was finally revealed those investors lost many millions of dollars as a result of defendants' fraud."
Four days after the second lawsuit was announced, on April 9th, the Schatz Nobel Izard Law Firm announced the third case seeking class action status on behalf of all persons who purchased or otherwise acquired securities of Lilly between March 28, 2002 and December 22, 2006.
This lawsuit also alleges that the same defendants violated securities laws by making misleading statements and specifically that they "contended that Zyprexa did not cause diabetes-related side effects," and later that, "Zyprexa did not cause more side effects than its competitors."
This press release also quotes the Times articles as showing "that defendants intentionally misrepresented the side effects of Zyprexa," and "suppressed and misrepresented data showing that Zyprexa causes weight gain, high blood sugar, and diabetes "
"In the five trading days during which the series of articles was published," the press release advises, "the price of Lilly's stock declined almost 6%."
Two days later, on April 11th, the Harwood Feffer Law Firm announced a fourth class action accusing the same defendants of making misleading statements and specifically that they failed to disclose: (i) dangerous side-effects resulting from the use of Zyprexa; (ii) the decade-long illegal campaign to increase sales by marketing Zyprexa for off-label uses not approved by the FDA, in violation of FDA regulations that proscribe such marketing.
As a result of these fraudulent business practices, the press release states, sales of Zyprexa rose from $3.69 billion to $4.42 billion between 2002 and 2004, and the value of stock increased from $43.75 per share to $76.95, between July 18, 2002 and May 7, 2004.
The release says defendants had knowledge of a link between Zyprexa and extreme weight gain and diabetes and when sued by private individuals who developed these adverse effects, "the Company adamantly refused to acknowledge any wrongdoing."
The Law Firm goes on to note that as public agencies raised warnings about Zyprexa, sales plummeted and stock price dropped from $76.95 per share to $50.34, between May 7, 2004 and October 25, 2004, amounting to a loss of market value of over $30 billion.
Subsequently, the press release alleges, after the Times published a series of articles the price of Lilly stock "collapsed" an additional $3.49 per share, or 6.4%, and amounted to a further loss of market value of approximately $3.5 billion.
Zyprexa was FDA approved for the limited use of treating adults with the most severe mental illnesses, schizophrenia and manic episodes of bipolar disorder, but it quickly became Lilly's best selling product.
In order to find that Lilly did not make the drug its top seller by illegally promoting it for off-label uses, a jury would have to believe the highly unlikely scenario that doctors in every field of medicine came up with the idea of prescribing a schizophrenia drug to patients as young as 2 and as old as 100, for every kind of condition imaginable from anxiety and attention deficit disorder to autism and dementia.
On April 25, 2007, the New York Times reported that the FDA was examining whether Lilly provided the agency with accurate data about the side effects of Zyprexa. However, that may be a dead issue in light of the fact that on May 4, 2007, Lilly issued a press release of its own to announce that Alex Azar II will be joining the company as a senior vice president, who until February 3, 2007, just happened to be the Deputy Secretary of the US Health and Human Services Department.
According to Lilly, "Azar supervised all operations of the HHS, including the regulation of food and drugs," and among others, agencies under his direction included the FDA.
Eli Lilly is not all that worried about personal injury lawsuits related to Zyprexa because the company has enough money to pay the relatively small pay-outs that arise from such actions, according to Attorney Barry Turner, a professor of law and ethics in the UK and a leading authority on consumer fraud litigation involving the pharmaceutical industry.
But he says the Medicaid fraud lawsuits filed by 9 states thus far, under the Federal and State False Claims Act are another matter. "The biggest penalties so far in Federal and State False Claims Act violations," Mr Turner reports, "were awarded against drug companies and there are very many more cases under seal."
But an even larger nightmare for top Lilly officials, he says, arises when a product like Zyprexa causes deaths and injuries to consumers and shareholders face huge losses including the millions of people who have their pensions invested in the company.
When a blockbuster drug is announced, Mr Turner says, it attracts huge investment and if that investment has been attracted to a product that Lilly knew was faulty, the company has risked shareholder funds beyond the pale.
This kind of behavior, he notes, is a Sarbox violation. The Sarbanes-Oxley Act was enacted to restore investor confidence in publicly traded companies in the wake of Enron and similar debacles by improving corporate accountability. Its official title is the "Public Company Accounting Reform and Investor Protection Act of 2002," named after its sponsors Senator Paul Sarbanes (D-MD) and Representative Michael G Oxley (R-OH), and is commonly referred to as SOX.
One of the features of SOX is the ability to bring an action against those who recklessly and fraudulently deal with stockholder's money and, "promoting the off label use of a drug with undeclared dangerous side effects, or being negligent as to such promotion, is the kind of behavior justifying an action under Sarbanes Oxley," according to Mr Turner.
"Those at the top of Eli Lilly," he states, "gambled with the lives of patients and the money of stockholders in equal bad faith when they engaged in fraudulent and dishonest behavior that allowed a dangerous drug to be marketed."
"The lifeblood of a business," he says, "is the investment that goes into it and in the case of Eli Lilly it means the investment of millions of shareholders."
"Anyone who defrauds them," he explains, "is defrauding people not business."
Mr Tuner says it is easy to think of shareholders as "rich lazy fat cats" living off the efforts of others but it is fundamentally wrong by ethical standards to think that if they are defrauded that perhaps they deserve it. "What needs to be understood," he says, "is that many millions of people who own no stock at all get defrauded in scams all the time."
"Those who pay into pension funds," he explains, "are vulnerable to the financial shenanigans not only of fund managers but of boards of companies and CEO's that fail to police the companies activities or in some cases actively encourage fraud and reckless business practices."
The worst of all legal nightmares resulting from the Zyprexa "shenanigans," occurred over a period of 9 days between April 2, 2007 and April 11, 2007, when not one, but 4 shareholder class action lawsuits were announced against Lilly and "certain of its officers and directors" filed in the US District Court for the Eastern District of New York, for violations of the Securities and Exchange Act alleging that the defendants hid the side effects of Zyprexa and engaged in illegal off-label marketing campaigns.
On April 2, 2007, the Law Firm of Schiffrin Barroway Topaz & Kessler, issued a press release to announce that a class action was filed on behalf of all securities purchasers of Lilly from March 28, 2002 and December 22, 2006, charging the defendants with disseminating false and misleading statements regarding Zyprexa.
More specifically, it alleges that they were aware of a "clear link" between Zyprexa and diabetes; and yet failed to warn the public and engaged in an illicit scheme to offset a drop in sales that was certain to occur, and did occur, when reports of Zyprexa's side effects emerged, by creating a marketing plan which included the evaluation and pursuit of sales for the drug based on "off-label" uses and that the off-label marketing program was a direct violation of Lilly's own code of conduct.
The complaint further alleges that concealing the side effects and engaging in a massive illegal marketing campaign potentially subjected Lilly to substantial regulatory fines, penalties and other legal action, compromising the company's overall financial condition and prospects.
The complaint reports that between 2002 and 2004, sales of Zyprexa grew from $3.69 billion to $4.42 billion, and that between July 18, 2002 and May 7, 2004, Lilly's stock value increased from $43.75 per share to $76.95.
Throughout the class period, the lawsuit says, Lilly had information about the link between Zyprexa and extreme weight gain and diabetes and in the face of mounting research linking the drug to diabetes and weight gain, and the lawsuits filed by persons who developed these conditions, "Lilly emphatically denied any such link."
The complaint alleges that when public warnings were issued about the safety of Zyprexa, sales slowed and between May 7, 2004 and October 25, 2004, stock prices dropped from $76.95 per share to $50.34, representing a loss of market capitalization of over $30 billion.
The press release cites reports in the New York Times between December 17 and 21, 2006, as disclosing for the "first time" that Lilly had engaged in a decade-long effort to play down the risks of Zyprexa; and actively marketed the drug for illegal off-label uses such as treating elderly patients with symptoms of dementia.
Therefore, the lawsuits alleges, the over $30 billion decline in stock value between May 7, 2004 and October 25, 2004 was the direct result of defendants' fraudulent conduct.
In addition it says, the publication of the Times articles caused another $3.49, or 6.4%, decline in stock value and represented a further market loss of approximately $3.5 billion.
Two days after the first class action was announced, on April 5th, the Lerach Coughlin Stoia Geller Rudman & Robbins Law Firm announced that another had been filed.
The second complaint also charges Lilly and certain of its officers and directors with violations of the Securities Exchange Act, and alleges that at the beginning of the class period, defendants contended that Zyprexa did not cause diabetes-related side effects and that once the clinical data rendered that position untenable, defendants argued instead that Zyprexa did not cause any more side effects than its competitors.
Eventually, the press release notes, more and more clinical data showed that, in fact, Zyprexa does cause such side effects and to a greater extent than its competitors and the "revelations sharply curtailed the sales growth of Zyprexa and resulted in thousands of product liability lawsuits against Lilly and hundreds of millions of dollars in settlements."
It also alleges that defendants intentionally suppressed and misrepresented data showing that Zyprexa causes weight gain, high blood sugar, and diabetes, citing the series of articles in the Times, with excerpted "documents detailing defendants' deception."
The release says the documents revealed that defendants intentionally misled patients, doctors, and investors and as a result, "the price of Lilly's stock declined almost 6% in the five trading days during which the series of articles was published."
The members of the class, it notes, invested in Lilly securities unaware that defendants' fraud had artificially inflated the prices of those securities and when "the truth was finally revealed those investors lost many millions of dollars as a result of defendants' fraud."
Four days after the second lawsuit was announced, on April 9th, the Schatz Nobel Izard Law Firm announced the third case seeking class action status on behalf of all persons who purchased or otherwise acquired securities of Lilly between March 28, 2002 and December 22, 2006.
This lawsuit also alleges that the same defendants violated securities laws by making misleading statements and specifically that they "contended that Zyprexa did not cause diabetes-related side effects," and later that, "Zyprexa did not cause more side effects than its competitors."
This press release also quotes the Times articles as showing "that defendants intentionally misrepresented the side effects of Zyprexa," and "suppressed and misrepresented data showing that Zyprexa causes weight gain, high blood sugar, and diabetes "
"In the five trading days during which the series of articles was published," the press release advises, "the price of Lilly's stock declined almost 6%."
Two days later, on April 11th, the Harwood Feffer Law Firm announced a fourth class action accusing the same defendants of making misleading statements and specifically that they failed to disclose: (i) dangerous side-effects resulting from the use of Zyprexa; (ii) the decade-long illegal campaign to increase sales by marketing Zyprexa for off-label uses not approved by the FDA, in violation of FDA regulations that proscribe such marketing.
As a result of these fraudulent business practices, the press release states, sales of Zyprexa rose from $3.69 billion to $4.42 billion between 2002 and 2004, and the value of stock increased from $43.75 per share to $76.95, between July 18, 2002 and May 7, 2004.
The release says defendants had knowledge of a link between Zyprexa and extreme weight gain and diabetes and when sued by private individuals who developed these adverse effects, "the Company adamantly refused to acknowledge any wrongdoing."
The Law Firm goes on to note that as public agencies raised warnings about Zyprexa, sales plummeted and stock price dropped from $76.95 per share to $50.34, between May 7, 2004 and October 25, 2004, amounting to a loss of market value of over $30 billion.
Subsequently, the press release alleges, after the Times published a series of articles the price of Lilly stock "collapsed" an additional $3.49 per share, or 6.4%, and amounted to a further loss of market value of approximately $3.5 billion.
Zyprexa was FDA approved for the limited use of treating adults with the most severe mental illnesses, schizophrenia and manic episodes of bipolar disorder, but it quickly became Lilly's best selling product.
In order to find that Lilly did not make the drug its top seller by illegally promoting it for off-label uses, a jury would have to believe the highly unlikely scenario that doctors in every field of medicine came up with the idea of prescribing a schizophrenia drug to patients as young as 2 and as old as 100, for every kind of condition imaginable from anxiety and attention deficit disorder to autism and dementia.
On April 25, 2007, the New York Times reported that the FDA was examining whether Lilly provided the agency with accurate data about the side effects of Zyprexa. However, that may be a dead issue in light of the fact that on May 4, 2007, Lilly issued a press release of its own to announce that Alex Azar II will be joining the company as a senior vice president, who until February 3, 2007, just happened to be the Deputy Secretary of the US Health and Human Services Department.
According to Lilly, "Azar supervised all operations of the HHS, including the regulation of food and drugs," and among others, agencies under his direction included the FDA.
Saturday, August 7, 2010
Off-Label Depakote Sales Stronger Than Ever
Evelyn Pringle February 11, 2007
The epilepsy drug, Depakote, earned Abbott Laboratories $384 million in the 4th quarter of 2006, and overall sales rose 18.5% to $1.2 billion last year.
The rising sales are a result of Depakote (valproate) being increasingly prescribed for conditions other than epilepsy like mood disorders, manic depression and migraines. Doctors are also prescribing Depakote as a mood stabilizer in off-label combinations with other drugs for uses that have never been FDA approved or tested for safety and efficacy.
Although in the US, drug companies are prohibited by law from promoting the sale of a drug for an off-label use, once a medication is FDA approved for once indication, doctors are free to prescribe it for other conditions if they believe it will be beneficial to a patient.
However, in recent years the rate of off-label prescribing has become epidemic and many drug companies have paid huge fines after being caught promoting drugs for unapproved uses and many more are currently under investigation for illegal marketing schemes.
In 2001, a study by the Agency for Healthcare Research and Quality (AHRQ) found that about 21% of prescriptions written in the US are for conditions not indicated on the label and cardiac medications and anticonvulsants were the most commonly prescribed for unapproved uses. Most off-label use, the study pointed out, occurs without scientific support.
Depakote is one of the drugs prescribed most often off-label, and experts say its not unusual to find patients on Depakote along with 3 or 4 other medications all at once.
On October 13, 2006, the FDA revised the labeling for Depakote to warn of adverse events associated with use of the drug during pregnancy and said that Depakote should only be considered for women of childbearing years if it was essential for the treatment of their condition and the risks and benefits were fully discussed with the patient.
According to the North American Antiepileptic Drug Pregnancy Registry, Depakote use during the first trimester of pregnancy is linked to a 4-fold increased risk of congenital malformations when compared with other antiepileptic drugs (AEDs). The rate malformations with infants exposed to Depakote was 10.7%, or 16 cases in 149 births.
The Registry is set up to determine the safety of anticonvulsants to help gauge the frequency of malformations, such as heart defects, spina bifida and cleft lip. Only major malformations are included in the Registry, defined as a structural abnormality of the infant with surgical, medical, or cosmetic importance.
The CDC reports that the risk of spina bifida among infants born to mothers receiving Depakote during the first trimester is estimated to be 1% to 2%, compared to 0.14% to 0.2% in the general population according to the American College of Obstetricians and Gynecologists.
Although Depakote is most strongly associated with neural tube defects, the FDA notes that other anomalies have also been reported, such as craniofacial defects, cardiovascular malformations, and anomalies involving various body systems with some fatal.
Drugs that cause malformations are known as teratogens. A teratogen can disturb the development of the fetus, halt the pregnancy, or permit the pregnancy to proceed but produce a congenital malformation or birth defect.
Due to the rate of off-label prescribing, pregnant women may be receiving Depakote for other indications and the FDA warns that the increased risk associated with Depakote in pregnant women treated for epilepsy likely reflects an increased risk in treatment for other conditions as well, such as migraines or bipolar disorder.
Depakote has now been moved into "Category C" for pregnant women, which means animal studies have shown an adverse effect and there are no adequate and well-controlled studies in pregnant women, or no animal studies have been conducted and there are no adequate and well-controlled studies in pregnant women.
In the case of Depakote, numerous animal studies have established drug-induced teratogenicity. Increased malformations, as well as growth retardation and death, have been found in rats, mice, rabbits, and monkeys following prenatal exposure to the drug, according to the FDA's information listed on Depakote.
Malformations of the skeletal system are the most common structural abnormalities observed in animals, but neural tube closure defects have been seen in mice exposed to plasma Depakote concentrations exceeding 2.3 times the upper limit of the human therapeutic range during periods of embryonic development.
An oral dose equal to about 50% of the maximum human daily dose administered to pregnant rats produced skeletal, cardiac, and urogenital malformations and growth retardation in the offspring. Behavioral deficits have also been reported in the offspring of rats given Depakote throughout most of the pregnancy.
An oral dose of approximately 2 times the maximum human daily dose produced skeletal and visceral malformations in rabbits exposed during organogenesis.
Skeletal malformations, growth retardation, and death have been observed in rhesus monkeys following administration of an oral dose equal to the maximum human daily dose during organogenesis.
The initial report from on-going human study titled, "Neurodevelopmental Effects of Antiepileptic Drugs," in the August 8, 2006, journal, Neurology, found that major congenital abnormalities were more common in infants exposed to Depakote than those exposed to one of 3 other AEDs.
A team of researchers led by Dr Kimford Meador, of the University of Florida, are conducting a study on pregnant women with treated for epilepsy from October 1999 to February 2004, receiving either Depakote, Dilantin, Lamictal, or Tegretol.
The initial report, focuses on the rate of serious adverse events including fetal death or major congenital malformations defined as structural abnormalities with surgical, medical, or cosmetic importance identified during pregnancy, at birth, between birth and 1 year, or at 73 weeks.
The researchers identified 6 fetal deaths and 22 malformations that included malformed hearts and genitals, cleft palate, and artery deformities, with 20.3% found in women taking Depakote.
Based on these initial findings, the researchers advised that Depakote should not be used as the first choice for women of childbearing potential, and if used, its dose should be limited when possible.
In an interview with Shawna Cutting, posted on Epilepsy.com, Dr Meador explained how he became interested in doing the study. "Over the years," he said, "I began to think that these effects might be dramatic in children while their brains are developing, because they could add up over many years."
"That made me think that the effect might be even greater in a fetus because brain development there is so rapid," he said.
"The process of physical growth and the attainment of intelligence and problem-solving ability that begins in infancy; any interruption of this process by a disease or disorder is called developmental delay," Dr Meador explained.
He said studies of animals clearly showed that some antiepileptic drugs could affect behavior of the offspring.
His on-going study will track children until they are 2 or 3, but says children need to be followed until they are at least 6. "This age is so important," Dr Meador said during the interview, "because this is when measures such as IQ begin to match up with adult measures."
"If you measure a child's IQ at 3 years of age," he explained, "it may not predict the child's development."
"But a measurement at 6 years of age," he said, "statistically will predict what will happen when this kid is an adult."
He also noted that this is an important point because children begin school at that age and whatever is going on will effect their learning and said, a "disturbing report" on a study from England suggested that Depakote was producing worse effects.
The epilepsy drug, Depakote, earned Abbott Laboratories $384 million in the 4th quarter of 2006, and overall sales rose 18.5% to $1.2 billion last year.
The rising sales are a result of Depakote (valproate) being increasingly prescribed for conditions other than epilepsy like mood disorders, manic depression and migraines. Doctors are also prescribing Depakote as a mood stabilizer in off-label combinations with other drugs for uses that have never been FDA approved or tested for safety and efficacy.
Although in the US, drug companies are prohibited by law from promoting the sale of a drug for an off-label use, once a medication is FDA approved for once indication, doctors are free to prescribe it for other conditions if they believe it will be beneficial to a patient.
However, in recent years the rate of off-label prescribing has become epidemic and many drug companies have paid huge fines after being caught promoting drugs for unapproved uses and many more are currently under investigation for illegal marketing schemes.
In 2001, a study by the Agency for Healthcare Research and Quality (AHRQ) found that about 21% of prescriptions written in the US are for conditions not indicated on the label and cardiac medications and anticonvulsants were the most commonly prescribed for unapproved uses. Most off-label use, the study pointed out, occurs without scientific support.
Depakote is one of the drugs prescribed most often off-label, and experts say its not unusual to find patients on Depakote along with 3 or 4 other medications all at once.
On October 13, 2006, the FDA revised the labeling for Depakote to warn of adverse events associated with use of the drug during pregnancy and said that Depakote should only be considered for women of childbearing years if it was essential for the treatment of their condition and the risks and benefits were fully discussed with the patient.
According to the North American Antiepileptic Drug Pregnancy Registry, Depakote use during the first trimester of pregnancy is linked to a 4-fold increased risk of congenital malformations when compared with other antiepileptic drugs (AEDs). The rate malformations with infants exposed to Depakote was 10.7%, or 16 cases in 149 births.
The Registry is set up to determine the safety of anticonvulsants to help gauge the frequency of malformations, such as heart defects, spina bifida and cleft lip. Only major malformations are included in the Registry, defined as a structural abnormality of the infant with surgical, medical, or cosmetic importance.
The CDC reports that the risk of spina bifida among infants born to mothers receiving Depakote during the first trimester is estimated to be 1% to 2%, compared to 0.14% to 0.2% in the general population according to the American College of Obstetricians and Gynecologists.
Although Depakote is most strongly associated with neural tube defects, the FDA notes that other anomalies have also been reported, such as craniofacial defects, cardiovascular malformations, and anomalies involving various body systems with some fatal.
Drugs that cause malformations are known as teratogens. A teratogen can disturb the development of the fetus, halt the pregnancy, or permit the pregnancy to proceed but produce a congenital malformation or birth defect.
Due to the rate of off-label prescribing, pregnant women may be receiving Depakote for other indications and the FDA warns that the increased risk associated with Depakote in pregnant women treated for epilepsy likely reflects an increased risk in treatment for other conditions as well, such as migraines or bipolar disorder.
Depakote has now been moved into "Category C" for pregnant women, which means animal studies have shown an adverse effect and there are no adequate and well-controlled studies in pregnant women, or no animal studies have been conducted and there are no adequate and well-controlled studies in pregnant women.
In the case of Depakote, numerous animal studies have established drug-induced teratogenicity. Increased malformations, as well as growth retardation and death, have been found in rats, mice, rabbits, and monkeys following prenatal exposure to the drug, according to the FDA's information listed on Depakote.
Malformations of the skeletal system are the most common structural abnormalities observed in animals, but neural tube closure defects have been seen in mice exposed to plasma Depakote concentrations exceeding 2.3 times the upper limit of the human therapeutic range during periods of embryonic development.
An oral dose equal to about 50% of the maximum human daily dose administered to pregnant rats produced skeletal, cardiac, and urogenital malformations and growth retardation in the offspring. Behavioral deficits have also been reported in the offspring of rats given Depakote throughout most of the pregnancy.
An oral dose of approximately 2 times the maximum human daily dose produced skeletal and visceral malformations in rabbits exposed during organogenesis.
Skeletal malformations, growth retardation, and death have been observed in rhesus monkeys following administration of an oral dose equal to the maximum human daily dose during organogenesis.
The initial report from on-going human study titled, "Neurodevelopmental Effects of Antiepileptic Drugs," in the August 8, 2006, journal, Neurology, found that major congenital abnormalities were more common in infants exposed to Depakote than those exposed to one of 3 other AEDs.
A team of researchers led by Dr Kimford Meador, of the University of Florida, are conducting a study on pregnant women with treated for epilepsy from October 1999 to February 2004, receiving either Depakote, Dilantin, Lamictal, or Tegretol.
The initial report, focuses on the rate of serious adverse events including fetal death or major congenital malformations defined as structural abnormalities with surgical, medical, or cosmetic importance identified during pregnancy, at birth, between birth and 1 year, or at 73 weeks.
The researchers identified 6 fetal deaths and 22 malformations that included malformed hearts and genitals, cleft palate, and artery deformities, with 20.3% found in women taking Depakote.
Based on these initial findings, the researchers advised that Depakote should not be used as the first choice for women of childbearing potential, and if used, its dose should be limited when possible.
In an interview with Shawna Cutting, posted on Epilepsy.com, Dr Meador explained how he became interested in doing the study. "Over the years," he said, "I began to think that these effects might be dramatic in children while their brains are developing, because they could add up over many years."
"That made me think that the effect might be even greater in a fetus because brain development there is so rapid," he said.
"The process of physical growth and the attainment of intelligence and problem-solving ability that begins in infancy; any interruption of this process by a disease or disorder is called developmental delay," Dr Meador explained.
He said studies of animals clearly showed that some antiepileptic drugs could affect behavior of the offspring.
His on-going study will track children until they are 2 or 3, but says children need to be followed until they are at least 6. "This age is so important," Dr Meador said during the interview, "because this is when measures such as IQ begin to match up with adult measures."
"If you measure a child's IQ at 3 years of age," he explained, "it may not predict the child's development."
"But a measurement at 6 years of age," he said, "statistically will predict what will happen when this kid is an adult."
He also noted that this is an important point because children begin school at that age and whatever is going on will effect their learning and said, a "disturbing report" on a study from England suggested that Depakote was producing worse effects.
GlaxoSmithKline Defamed With Truth About Paxil
Evelyn Pringle January 31, 2007
GlaxoSmithKline has labeled the allegations made in a Panorama television program that said the company had suppressed the results of clinical trials that showed Paxil was ineffective and caused children to become suicidal "defamatory."
According to the January 30, 2007, Guardian, an official at the company said Glaxo had looked into taking legal action, "but that there wouldn't be much to gain from taking action against the BBC".
The Guardian also reported that Glaxo "utterly rejects any suggestion that it has improperly withheld drug trial information."
This is not news. Glaxo has falsely denied these assertions probably 100 times in the past from one end of the globe to the other. If Glaxo files a lawsuit against the BBC, it might as well file a worldwide class action against all the other "defamers" who for some reason or another repeated the exact same allegations.
The BBC has broadcast several Panorama programs on Glaxo's marketing of Paxil for children even after the company's own research showed the drug to be ineffective and dangerous with children. The latest program titled, "Secrets of the Drug Trials," was broadcast on January 29, 2007.
Glaxo's worn-out declarations of innocence can only be adequately responded to by highlighting a few of the historical moments in Paxil's never-ending trail of misery.
A good place to start is Wyoming in the year 2000, with the trial involving the case of Donald Schell, who had been on Paxil just two days when he killed his wife, daughter and infant granddaughter before killing himself.
His surviving son-in-law, Tim Tobin, brought a wrongful death lawsuit against Glaxo.
Prior to the trial, an expert for the plaintiff, Dr David Healy, a well-recognized expert on selective seratonin reuptake inhibitor antidepressants (SSRIs), was given access to Glaxo's files on the Paxil studies.
He spent two days reviewing several hundred thousand documents looking for reports on the trials conducted on "healthy volunteers." Healthy volunteer refers to study participants who were not depressed or mentally ill to begin with before taking a drug. If it was shown that suicidality was evident in health volunteers it would disprove Glaxo's theory that suicide was caused by the underlying illness of depression.
Dr Healy was interested in these trials because he knew of recent studies that had surfaced on another SSRI, Pfizer's Zoloft, that showed the drugs could trigger suicidality in healthy volunteers. When he finally found the right files, Dr Healy told the BBC:
"It seemed clear that some people that went on the drugs had no major problems, but equally clear that others who went on the drug ended up more restless, in a state of mental turmoil, complaining about dreams, nightmares and a range of things like this. These don't seem to have been explored further in any great detail."
Dr Healy discovered that one in 4 healthy volunteers suffered this mental turmoil even when they were on normal doses of Paxil and had only been taking it for a few days.
In addition, he found the agitation was worse when the dose was increased and cleared up when Paxil was stopped, only to reemerge when it was started again. There had also been a suicide in the program, and in one healthy volunteer study, Paxil was linked to withdrawal effects in around 85% of subjects.
After hearing the testimony of Dr Healy, the Wyoming jury awarded Mr Tobin more than $6 million in damages in the first jury verdict against a drug maker for the psychiatric side effects caused by an SSRI.
Going up against SSRI makers on behalf of SSRI victims has cost Dr Healy plenty. In 2000, he accepted a position at the University of Toronto, but in the wake of a lecture at the University in November 2000, in which he mentioned that there had been an almost complete lack of research on the risk of suicide associated with SSRIs, Dr Healy was informed that he had lost his job before it even began.
The next historical moment worth noting in the Paxil saga took place in June 2004, when New York's attorney general, Elliot Spitzer, filed charges of consumer fraud against Glaxo and alleged that the company had "repeatedly" concealed damaging information in Paxil studies conducted on children.
The complaint stated that, "starting in 1998, GSK engaged in a concerted effort to withhold negative information concerning Paxil and misrepresented data concerning Paxil's safety and efficacy when prescribed for depression in children and adolescents."
It also alleged an internal 1999, document showed that the company intended to "manage the dissemination of data in order to minimize any potential negative commercial impact.''
The lawsuit charged that Glaxo conducted at least 5 studies on Paxil with children, but only published one. A study referred to as Study 377, noted that some children exhibited suicidal behaviors and attempts to commit suicide. Referring to that study, and also Study 329, the complaint alleged, an internal Glaxo memo acknowledged that Paxil "failed to demonstrate a statistically significant difference from placebo on the primary efficacy measures."
Glaxo might want to add Mr Spitzer as a defendant in the worldwide class action for his "defamatory" remarks, made in print no less. According to a June 2, 2004, press release by Mr Spitzer, by concealing negative studies, Glaxo made out like a bandit in 2002, with more than 2 million pediatric prescriptions for Paxil written in the US. "Prescriptions for Paxil to treat mood disorders in children and adolescents," Mr Spitzer said, "translated into US sales for GSK of approximately $55 million in 2002 alone."
The lawsuit also alleged that Glaxo misrepresented the results of the company's own research to its sales representatives who promoted Paxil to physicians and portrayed the drug as having "remarkable efficacy and safety in the treatment of adolescent depression," when in fact, the studies did not demonstrate that Paxil was effective in treating children and showed the possibility of increased risk of suicidal thoughts and acts in adolescents.
The suit further alleged that Glaxo failed to disclose this information in "Medical Information Letters" that it sent to physicians, and thus deprived physicians of the information needed to evaluate the risks and benefits of prescribing Paxil for children and deprived children of the benefit of their doctor's professional judgment.
In August 2004, to settle the charges that were based on the same allegations made during the Panorama program that Glaxo now claims are "defamatory," Glaxo agreed to pay $2.5 million and to publicly disclose all clinical studies.
Glaxo's largest clinical trial on the use of Paxil with children was conducted in the US in the 1990s, and was called Study 329. Child psychiatrist, Dr Neal Ryan, of the University of Pittsburgh, was paid by Glaxo and was listed as co-author of the study.
In 2002, Dr Ryan also gave a talk on childhood depression at a medical conference sponsored by Glaxo and said that Paxil would be a suitable treatment for children. He later told Panorama reporter, Shelley Jofre, that Paxil had probably lowered rather than raised suicide rates.
But an internal company email penned by a public relations executive working for Glaxo describes Study 329 differently. "Originally we had planned to do extensive media relations surrounding this study," it said, "until we actually viewed the results."
"Essentially the study did not really show it was effective in treating adolescent depression," the email stated, "which is not something we want to publicise."
However, the manipulated results from Study 329 were in fact published in the Journal of American Child Adolescent Psychiatry in 2001, with the positive spin stating, "Paxil is generally well tolerated and effective for major depression in adolescents."
Another publication that Glaxo might want to add as a defendant in its class action against the world would be the Canadian Medical Association Journal. In March 2004, the Journal printed excerpts from an internal Glaxo memo to illustrate how the company had withheld studies from regulatory agencies that showed the ineffectiveness of Paxil with children which stated in part: "It would be unacceptable to include a statement that efficacy had not been demonstrated, as this would undermine the profile of paroxetine".
A television program in the US could be added to the list of "defamers" as well. Back in December 2004, ABC's "Primetime Live," also said it had obtained hidden Glaxo studies and reported that some children in the studies showed the same types of suicidal thoughts and behaviors that parents had for years claimed their children were exhibiting.
According to these documents, Primetime said, internal studies showed Paxil had little or no effect in treating depression in children and adolescents and as far back as 1997, the company was aware of suicide related behaviors in young patients taking the drug.
In spite of this information, Primetime reported, Glaxo distributed a memo to its sales force in 2001 touting the drug's "remarkable efficacy and safety in the treatment of adolescent depression."
And last but not least, another "defamer" would appear to be the US Congress. It too claimed that Glaxo hid negative studies in the name of profits. "This is about money," said Representative, Henry Waxman (D-CA), who was on a congressional committee investigating SSRI makers at the time.
"This is not about science," he stated, "because what they're doing is withholding the scientific information, suppressing the studies that could have a negative impact on their sales and their profits."
GlaxoSmithKline has labeled the allegations made in a Panorama television program that said the company had suppressed the results of clinical trials that showed Paxil was ineffective and caused children to become suicidal "defamatory."
According to the January 30, 2007, Guardian, an official at the company said Glaxo had looked into taking legal action, "but that there wouldn't be much to gain from taking action against the BBC".
The Guardian also reported that Glaxo "utterly rejects any suggestion that it has improperly withheld drug trial information."
This is not news. Glaxo has falsely denied these assertions probably 100 times in the past from one end of the globe to the other. If Glaxo files a lawsuit against the BBC, it might as well file a worldwide class action against all the other "defamers" who for some reason or another repeated the exact same allegations.
The BBC has broadcast several Panorama programs on Glaxo's marketing of Paxil for children even after the company's own research showed the drug to be ineffective and dangerous with children. The latest program titled, "Secrets of the Drug Trials," was broadcast on January 29, 2007.
Glaxo's worn-out declarations of innocence can only be adequately responded to by highlighting a few of the historical moments in Paxil's never-ending trail of misery.
A good place to start is Wyoming in the year 2000, with the trial involving the case of Donald Schell, who had been on Paxil just two days when he killed his wife, daughter and infant granddaughter before killing himself.
His surviving son-in-law, Tim Tobin, brought a wrongful death lawsuit against Glaxo.
Prior to the trial, an expert for the plaintiff, Dr David Healy, a well-recognized expert on selective seratonin reuptake inhibitor antidepressants (SSRIs), was given access to Glaxo's files on the Paxil studies.
He spent two days reviewing several hundred thousand documents looking for reports on the trials conducted on "healthy volunteers." Healthy volunteer refers to study participants who were not depressed or mentally ill to begin with before taking a drug. If it was shown that suicidality was evident in health volunteers it would disprove Glaxo's theory that suicide was caused by the underlying illness of depression.
Dr Healy was interested in these trials because he knew of recent studies that had surfaced on another SSRI, Pfizer's Zoloft, that showed the drugs could trigger suicidality in healthy volunteers. When he finally found the right files, Dr Healy told the BBC:
"It seemed clear that some people that went on the drugs had no major problems, but equally clear that others who went on the drug ended up more restless, in a state of mental turmoil, complaining about dreams, nightmares and a range of things like this. These don't seem to have been explored further in any great detail."
Dr Healy discovered that one in 4 healthy volunteers suffered this mental turmoil even when they were on normal doses of Paxil and had only been taking it for a few days.
In addition, he found the agitation was worse when the dose was increased and cleared up when Paxil was stopped, only to reemerge when it was started again. There had also been a suicide in the program, and in one healthy volunteer study, Paxil was linked to withdrawal effects in around 85% of subjects.
After hearing the testimony of Dr Healy, the Wyoming jury awarded Mr Tobin more than $6 million in damages in the first jury verdict against a drug maker for the psychiatric side effects caused by an SSRI.
Going up against SSRI makers on behalf of SSRI victims has cost Dr Healy plenty. In 2000, he accepted a position at the University of Toronto, but in the wake of a lecture at the University in November 2000, in which he mentioned that there had been an almost complete lack of research on the risk of suicide associated with SSRIs, Dr Healy was informed that he had lost his job before it even began.
The next historical moment worth noting in the Paxil saga took place in June 2004, when New York's attorney general, Elliot Spitzer, filed charges of consumer fraud against Glaxo and alleged that the company had "repeatedly" concealed damaging information in Paxil studies conducted on children.
The complaint stated that, "starting in 1998, GSK engaged in a concerted effort to withhold negative information concerning Paxil and misrepresented data concerning Paxil's safety and efficacy when prescribed for depression in children and adolescents."
It also alleged an internal 1999, document showed that the company intended to "manage the dissemination of data in order to minimize any potential negative commercial impact.''
The lawsuit charged that Glaxo conducted at least 5 studies on Paxil with children, but only published one. A study referred to as Study 377, noted that some children exhibited suicidal behaviors and attempts to commit suicide. Referring to that study, and also Study 329, the complaint alleged, an internal Glaxo memo acknowledged that Paxil "failed to demonstrate a statistically significant difference from placebo on the primary efficacy measures."
Glaxo might want to add Mr Spitzer as a defendant in the worldwide class action for his "defamatory" remarks, made in print no less. According to a June 2, 2004, press release by Mr Spitzer, by concealing negative studies, Glaxo made out like a bandit in 2002, with more than 2 million pediatric prescriptions for Paxil written in the US. "Prescriptions for Paxil to treat mood disorders in children and adolescents," Mr Spitzer said, "translated into US sales for GSK of approximately $55 million in 2002 alone."
The lawsuit also alleged that Glaxo misrepresented the results of the company's own research to its sales representatives who promoted Paxil to physicians and portrayed the drug as having "remarkable efficacy and safety in the treatment of adolescent depression," when in fact, the studies did not demonstrate that Paxil was effective in treating children and showed the possibility of increased risk of suicidal thoughts and acts in adolescents.
The suit further alleged that Glaxo failed to disclose this information in "Medical Information Letters" that it sent to physicians, and thus deprived physicians of the information needed to evaluate the risks and benefits of prescribing Paxil for children and deprived children of the benefit of their doctor's professional judgment.
In August 2004, to settle the charges that were based on the same allegations made during the Panorama program that Glaxo now claims are "defamatory," Glaxo agreed to pay $2.5 million and to publicly disclose all clinical studies.
Glaxo's largest clinical trial on the use of Paxil with children was conducted in the US in the 1990s, and was called Study 329. Child psychiatrist, Dr Neal Ryan, of the University of Pittsburgh, was paid by Glaxo and was listed as co-author of the study.
In 2002, Dr Ryan also gave a talk on childhood depression at a medical conference sponsored by Glaxo and said that Paxil would be a suitable treatment for children. He later told Panorama reporter, Shelley Jofre, that Paxil had probably lowered rather than raised suicide rates.
But an internal company email penned by a public relations executive working for Glaxo describes Study 329 differently. "Originally we had planned to do extensive media relations surrounding this study," it said, "until we actually viewed the results."
"Essentially the study did not really show it was effective in treating adolescent depression," the email stated, "which is not something we want to publicise."
However, the manipulated results from Study 329 were in fact published in the Journal of American Child Adolescent Psychiatry in 2001, with the positive spin stating, "Paxil is generally well tolerated and effective for major depression in adolescents."
Another publication that Glaxo might want to add as a defendant in its class action against the world would be the Canadian Medical Association Journal. In March 2004, the Journal printed excerpts from an internal Glaxo memo to illustrate how the company had withheld studies from regulatory agencies that showed the ineffectiveness of Paxil with children which stated in part: "It would be unacceptable to include a statement that efficacy had not been demonstrated, as this would undermine the profile of paroxetine".
A television program in the US could be added to the list of "defamers" as well. Back in December 2004, ABC's "Primetime Live," also said it had obtained hidden Glaxo studies and reported that some children in the studies showed the same types of suicidal thoughts and behaviors that parents had for years claimed their children were exhibiting.
According to these documents, Primetime said, internal studies showed Paxil had little or no effect in treating depression in children and adolescents and as far back as 1997, the company was aware of suicide related behaviors in young patients taking the drug.
In spite of this information, Primetime reported, Glaxo distributed a memo to its sales force in 2001 touting the drug's "remarkable efficacy and safety in the treatment of adolescent depression."
And last but not least, another "defamer" would appear to be the US Congress. It too claimed that Glaxo hid negative studies in the name of profits. "This is about money," said Representative, Henry Waxman (D-CA), who was on a congressional committee investigating SSRI makers at the time.
"This is not about science," he stated, "because what they're doing is withholding the scientific information, suppressing the studies that could have a negative impact on their sales and their profits."
Drug Eluting Stent Patients Beware
Evelyn Pringle January 24, 2007
Drug eluting stents were promoted as working so much better than the old bare metal stents that 6 million people worldwide have received them in the few years since the arrived on the market.
"It was a modern record for any medical device," the Boston Globe reported on December 4, 2006. Some 2 to 3 million people in the US now carry one of these devices in an artery, according to FDA estimates, with new implants topping 900,000 per year.
Only two brands of DES are sold in the US, the Taxus, by Boston Scientific, and the Cypher, by Johnson & Johnson's Cordis Division.
The trials submitted by the DES makers to obtain FDA approval for use in limited procedures with non-complex patients with single-vessel heart disease, involved a low risk population. However, off-label DES use for procedures not approved by the FDA has become rampant and according to the agency:
"It is estimated that a majority of DES are implanted in lesions outside of their current indications for use, such as in-stent restenosis lesions, bifurcation lesions, coronary artery bypass grafts, acute myocardial infarction, chronic total occlusions, overlapping and multiple stents per vessel and in patients with multivessel disease and chronic renal insufficiency."
Surgeons have been implanting the new devices in every kind of heart patient. And for good reason. The stenting business represents maga bucks to device makers, hospitals and surgeons alike. In the US, the implant procedure itself costs $38,203, according to a report by the Associated Press on December 26, 2006.
But as has been the case with so many pharmaceutical products in recent years, after being massively promoted, and implanted in millions of patients for indications not approved, DES are proving to be no better than the bare metal stents, and in fact research has shown them to worse because they come with more adverse reactions.
In early December 2006, the FDA's Circulatory System Devices Advisory Committee held a public meeting to review data on thrombosis both when DES were used according to their label and when they are implanted off-label for unapproved uses, and to address the appropriate duration for the use of the blood-thinning drug, Plavix, with DES patients.
In the briefing provided to the Committee before the hearing, the FDA informed the panel that recent presentations at scientific meetings had indicated a small but significant increase in the rates of death or myocardial infarction, and non-cardiac mortality, in DES patients when compared to patients who received bare metal stents.
The briefing included a specific discussion of presentations made at the Transcatheter Cardiovascular Therapeutics meeting, in October 2006, where doctors, Martin Leon and Gregg Stone, presented a meta-analyses of patient data from the Cypher and Taxus clinical trails.
Based on these analyses, Dr Stuart Pocock reported that after one year, five Cypher patients, compared to no bare metal patients, had experienced late thrombosis, and with the Taxus, thrombosis occurred in nine patients after one year compared with two bare metal stent patients.
Last year, the Swiss government commissioned a study to determine whether the DES were worth their price of between $2,200 and $2,700, when compared to the $600 to $800 for bare metal stents, and also to test how long Plavix should be prescribed to patients after the implantation of a DES to prevent blood clots from developing.
The study appeared in the December 19, 2006, Journal of the American College of Cardiology, and reported that patients with DES had double the risk of cardiac problems after stopping Plavix compared to patients with bare metal stents.
The Swiss researchers, led by Dr Matthias Pfisterer, found that when patients stop taking Plavix, they had a small but serious risk of blood clots leading to death or heart attack.
The lead author noted that the majority of DES implants in the study were off-label. "About two-thirds of our patients were really treated with off-label use of drug-eluting stents," Dr Pfisterer told WebMD on December 5, 2006.
"The FDA label says these are only for stable patients with limited disease," he notes. "But, in fact," he told WebMD, "most doctors who use drug-eluting stents use them in unstable patients and in more complex disease."
In an editorial accompanying the Pfisterer study, Dr Robert Califf and Dr Robert Harrington, warned that research on DES has not kept up with clinical realities. "As is frequently seen with new cardiac devices," they wrote, "rapid increase in clinical adoption quickly outstripped what is known about the device from limited clinical trials."
Medical professionals say an important point to keep in mind when considering the risks associated with the DES is that these devices have only been on the market in the US for less than four years and that many more unknown risks could surface in years to come.
More problems may have already surfaced according to Dr Joseph Muhlestein, a professor at the University of Utah. He told ABC New's Healthday reporter on December 4, 2006, that his research group has followed patients receiving DES implants very carefully and has found "something we don't understand."
As expected, he said, the DES did reduce artery closure at the site where they were implanted, but the incidence of artery problems at other sites occurred "significantly more often than when we used bare-metal stents," he told Healthday.
So, the overall incidence of artery problems ended up being the same, regardless of which type of stent was implanted, Dr Muhlestein said.
It is possible that the problem occurred because DES were used on more high-risk patients, he noted. But it's also possible, he said, that the DES interfered with the endothelium, the delicate tissue that lines the arteries.
These doubts have caused some doctors to cut back on DES use. "We used to use them in 90 percent of cases," Dr Muhlestein told Healthday. "Now, it's about 40 percent."
Finally, experts are warning that if unexpected health problems do develop in patients already implanted with the DES, removal of the stent is not possible because once it is placed in the body, the tissue in the artery grows over the stent.
Drug eluting stents were promoted as working so much better than the old bare metal stents that 6 million people worldwide have received them in the few years since the arrived on the market.
"It was a modern record for any medical device," the Boston Globe reported on December 4, 2006. Some 2 to 3 million people in the US now carry one of these devices in an artery, according to FDA estimates, with new implants topping 900,000 per year.
Only two brands of DES are sold in the US, the Taxus, by Boston Scientific, and the Cypher, by Johnson & Johnson's Cordis Division.
The trials submitted by the DES makers to obtain FDA approval for use in limited procedures with non-complex patients with single-vessel heart disease, involved a low risk population. However, off-label DES use for procedures not approved by the FDA has become rampant and according to the agency:
"It is estimated that a majority of DES are implanted in lesions outside of their current indications for use, such as in-stent restenosis lesions, bifurcation lesions, coronary artery bypass grafts, acute myocardial infarction, chronic total occlusions, overlapping and multiple stents per vessel and in patients with multivessel disease and chronic renal insufficiency."
Surgeons have been implanting the new devices in every kind of heart patient. And for good reason. The stenting business represents maga bucks to device makers, hospitals and surgeons alike. In the US, the implant procedure itself costs $38,203, according to a report by the Associated Press on December 26, 2006.
But as has been the case with so many pharmaceutical products in recent years, after being massively promoted, and implanted in millions of patients for indications not approved, DES are proving to be no better than the bare metal stents, and in fact research has shown them to worse because they come with more adverse reactions.
In early December 2006, the FDA's Circulatory System Devices Advisory Committee held a public meeting to review data on thrombosis both when DES were used according to their label and when they are implanted off-label for unapproved uses, and to address the appropriate duration for the use of the blood-thinning drug, Plavix, with DES patients.
In the briefing provided to the Committee before the hearing, the FDA informed the panel that recent presentations at scientific meetings had indicated a small but significant increase in the rates of death or myocardial infarction, and non-cardiac mortality, in DES patients when compared to patients who received bare metal stents.
The briefing included a specific discussion of presentations made at the Transcatheter Cardiovascular Therapeutics meeting, in October 2006, where doctors, Martin Leon and Gregg Stone, presented a meta-analyses of patient data from the Cypher and Taxus clinical trails.
Based on these analyses, Dr Stuart Pocock reported that after one year, five Cypher patients, compared to no bare metal patients, had experienced late thrombosis, and with the Taxus, thrombosis occurred in nine patients after one year compared with two bare metal stent patients.
Last year, the Swiss government commissioned a study to determine whether the DES were worth their price of between $2,200 and $2,700, when compared to the $600 to $800 for bare metal stents, and also to test how long Plavix should be prescribed to patients after the implantation of a DES to prevent blood clots from developing.
The study appeared in the December 19, 2006, Journal of the American College of Cardiology, and reported that patients with DES had double the risk of cardiac problems after stopping Plavix compared to patients with bare metal stents.
The Swiss researchers, led by Dr Matthias Pfisterer, found that when patients stop taking Plavix, they had a small but serious risk of blood clots leading to death or heart attack.
The lead author noted that the majority of DES implants in the study were off-label. "About two-thirds of our patients were really treated with off-label use of drug-eluting stents," Dr Pfisterer told WebMD on December 5, 2006.
"The FDA label says these are only for stable patients with limited disease," he notes. "But, in fact," he told WebMD, "most doctors who use drug-eluting stents use them in unstable patients and in more complex disease."
In an editorial accompanying the Pfisterer study, Dr Robert Califf and Dr Robert Harrington, warned that research on DES has not kept up with clinical realities. "As is frequently seen with new cardiac devices," they wrote, "rapid increase in clinical adoption quickly outstripped what is known about the device from limited clinical trials."
Medical professionals say an important point to keep in mind when considering the risks associated with the DES is that these devices have only been on the market in the US for less than four years and that many more unknown risks could surface in years to come.
More problems may have already surfaced according to Dr Joseph Muhlestein, a professor at the University of Utah. He told ABC New's Healthday reporter on December 4, 2006, that his research group has followed patients receiving DES implants very carefully and has found "something we don't understand."
As expected, he said, the DES did reduce artery closure at the site where they were implanted, but the incidence of artery problems at other sites occurred "significantly more often than when we used bare-metal stents," he told Healthday.
So, the overall incidence of artery problems ended up being the same, regardless of which type of stent was implanted, Dr Muhlestein said.
It is possible that the problem occurred because DES were used on more high-risk patients, he noted. But it's also possible, he said, that the DES interfered with the endothelium, the delicate tissue that lines the arteries.
These doubts have caused some doctors to cut back on DES use. "We used to use them in 90 percent of cases," Dr Muhlestein told Healthday. "Now, it's about 40 percent."
Finally, experts are warning that if unexpected health problems do develop in patients already implanted with the DES, removal of the stent is not possible because once it is placed in the body, the tissue in the artery grows over the stent.
Experts Predict Many Cases of Permax Heart Valve Damage
Evelyn Pringle January 21, 2007
Nearly three years ago, HealthDay News reported that a study had confirmed previous findings that the drug, Permax, used to treat Parkinson's disease, could damage heart valves and surgery would be needed to correct the problem.
The April 28, 2004, report quoted the lead researcher, Dr Richard Dewey Jr, an associate professor from the University of Texas Southwestern Medical Center, as saying he believed the drug should be taken off the market.
Permax (pergolide) belongs to a class of drugs known as dopamine agonists. Dopamine helps regulate movement and balance. People with Parkinson's suffer from a shortage of dopamine and Permax stimulates nerves in the brain that would normally be stimulated by dopamine. The drug has also been prescribed to treat restless leg syndrome.
Two years earlier, in December 2002, doctors at the Mayo Clinic reported heart valve disease in three patients who had been taking Permax for several years, similar to the damage found in patients who took the Fen-Phen diet drugs.
The 3 cases involved women aged 61, 72, and 74, with no history of heart disease, who had been taking Permax for between three and seven years to treat Parkinson's symptoms. They were all diagnosed with serious valve disease and two required replacement surgery.
As a follow-up to the earlier reports of valve damage in Permax patients, Dr Dewey, and his fellow researchers sent out 200 letters to people who were known to be taking Permax for Parkinson's to determine whether the reports were isolated cases or a common side effect of the drug, and to suggest that patients should switch to anther drug. Patients who wanted to continue taking Permax were urged to have an echocardiogram, to check for heart valve damage.
For the Dewey study, echocardiograms were performed on 46 patients, and then compared the test results from a similarly-aged healthy comparison group. The study found that 89% of the patients receiving Permax had evidence of leaky heart valves, called valvular insufficiency, and Permax patients were up to 18 times more likely to have significant leakage in at least one valve, than patients in the comparison group.
Blood is pumped through the heart in only one direction, according to the Texas Heart Institute. Heart valves play a key role in this one-way blood flow, opening and closing with each heartbeat. Pressure changes on either side of the valves cause them to open their flap-like "doors" at just the right time, then close tightly to prevent a backflow of blood. There are 4 valves in the heart:
* Tricuspid valve
* Pulmonary valve
* Mitral valve
* Aortic valve
Valvular insufficiency occurs when the heart valves do not close properly. It forces the heart to work harder to circulate the blood and can lead to serious problems such as heart attack or heart failure, according to WebMD. Symptoms of heart valve disease include:
* Shortness of breath and/or difficulty breathing
* Weakness or dizziness
* Chest pain or pressure
* Heart palpitations
* Swelling of ankles, feet, or abdomen
* Rapid weight gain
Two new studies published in the January 4, 2007, New England Journal of Medicine, report that the number of Parkinson patients on Permax who have developed heart valve damage is higher than expected.
In one study titled, "Dopamine Agonists and the Risk of Cardiac-Valve Regurgitation," researchers led by Dr Renzo Zanettini, in Milan, Italy obtained echocardiograms from 155 patients taking various Parkinson's drugs, and 90 healthy patients for a comparison group.
The study found moderate to severe valve problems in more than 23% of the patients receiving Permax compared to less than 6% of the patients in the comparison group.
The second study found that Permax users were five to seven times more likely to have leaky heart valves than patients taking other types of Parkinson's drugs, and patients taking the highest doses of Permax had a 37 times greater risk of valve damage. In this study, Dr Rene Schade and colleagues in Berlin and Montreal reviewed records from over 11,400 patients with Parkinson's disease in the UK.
"This is not a rare side effect," says Dr Bryan Roth, a pharmacology professor at the University of North Carolina, who wrote an editorial accompanying the reports in the NEJM. "That's an extraordinarily high incidence," he warns. "That makes this a serious problem."
Experts note that there are no medications that can be used to reverse valve damage and replacement surgery is the only solution.
Dr Roth published a paper several years ago warning that Permax appeared to trigger the same heart valve problems as the Fen-Phen combination of the drugs, Pondimin and Redux, which were pulled off the market in 1997, after they were linked to valve disease.
The findings of the new Permax studies could potentially represent a public health crisis. The drugs, available in generic form from a variety of producers, "have been around a long time, and a large number of people have potentially been exposed to them," said Dr Michael Okun, medical director of the National Parkinson Foundation, in the January 4, 2007 LA Times.
Permax came on the market in the US about 14 years ago, and an estimated half million people had already taken the drug by the time its maker, Eli Lilly, added valve damage to the side effects listed on the labeling in late 2003. The warning included the statement: "Some patients have required valve replacement, and deaths have been reported," but at the same time, Lilly claimed that the problem only occurred in five out of every 100,000 Permax users.
The drug is now marketed in the US by Valeant Pharmaceuticals.
Heart valve damage is an extremely serious medical condition that is both life-threatening and costly to treat. During valve replacement surgery, the breastbone is divided, the heart is stopped, and blood is sent through a heart-lung machine. Because the heart or aorta must be opened, it requires open heart surgery, according to the Texas Heart Institute.
The two kinds of valves used for replacement surgery are mechanical valves made from materials such as plastic or metal, and biological valves made from animal tissue or human tissue from a donated heart.
Mechanical valves are stronger and last longer but because blood tends to stick to them and create blood clots, patients need to take blood-thinning drugs for the rest of their lives. And because these medicines increase the risk of bleeding within the body, patients must always wear a medical alert bracelet so medical professionals will know they are taking a blood-thinning medication.
Patients with biological valves usually do not have to take blood-thinning drugs but because the valves are not as strong as mechanical valves patients may need have the valve replaced every 10 years.
Following surgery, a patient can expect to stay in the hospital for about a week, including at least 1 to 3 days in the Intensive Care Unit, the Texas Institute says. Patients with an office job, can usually go back to work in 4 to 6 weeks but those with more physically demanding jobs may need to be off work longer.
In addition to switching to another drug to treat Parkinson's disease, medical experts are advising all Permax patients to undergo testing to check for heart valve damage.
Nearly three years ago, HealthDay News reported that a study had confirmed previous findings that the drug, Permax, used to treat Parkinson's disease, could damage heart valves and surgery would be needed to correct the problem.
The April 28, 2004, report quoted the lead researcher, Dr Richard Dewey Jr, an associate professor from the University of Texas Southwestern Medical Center, as saying he believed the drug should be taken off the market.
Permax (pergolide) belongs to a class of drugs known as dopamine agonists. Dopamine helps regulate movement and balance. People with Parkinson's suffer from a shortage of dopamine and Permax stimulates nerves in the brain that would normally be stimulated by dopamine. The drug has also been prescribed to treat restless leg syndrome.
Two years earlier, in December 2002, doctors at the Mayo Clinic reported heart valve disease in three patients who had been taking Permax for several years, similar to the damage found in patients who took the Fen-Phen diet drugs.
The 3 cases involved women aged 61, 72, and 74, with no history of heart disease, who had been taking Permax for between three and seven years to treat Parkinson's symptoms. They were all diagnosed with serious valve disease and two required replacement surgery.
As a follow-up to the earlier reports of valve damage in Permax patients, Dr Dewey, and his fellow researchers sent out 200 letters to people who were known to be taking Permax for Parkinson's to determine whether the reports were isolated cases or a common side effect of the drug, and to suggest that patients should switch to anther drug. Patients who wanted to continue taking Permax were urged to have an echocardiogram, to check for heart valve damage.
For the Dewey study, echocardiograms were performed on 46 patients, and then compared the test results from a similarly-aged healthy comparison group. The study found that 89% of the patients receiving Permax had evidence of leaky heart valves, called valvular insufficiency, and Permax patients were up to 18 times more likely to have significant leakage in at least one valve, than patients in the comparison group.
Blood is pumped through the heart in only one direction, according to the Texas Heart Institute. Heart valves play a key role in this one-way blood flow, opening and closing with each heartbeat. Pressure changes on either side of the valves cause them to open their flap-like "doors" at just the right time, then close tightly to prevent a backflow of blood. There are 4 valves in the heart:
* Tricuspid valve
* Pulmonary valve
* Mitral valve
* Aortic valve
Valvular insufficiency occurs when the heart valves do not close properly. It forces the heart to work harder to circulate the blood and can lead to serious problems such as heart attack or heart failure, according to WebMD. Symptoms of heart valve disease include:
* Shortness of breath and/or difficulty breathing
* Weakness or dizziness
* Chest pain or pressure
* Heart palpitations
* Swelling of ankles, feet, or abdomen
* Rapid weight gain
Two new studies published in the January 4, 2007, New England Journal of Medicine, report that the number of Parkinson patients on Permax who have developed heart valve damage is higher than expected.
In one study titled, "Dopamine Agonists and the Risk of Cardiac-Valve Regurgitation," researchers led by Dr Renzo Zanettini, in Milan, Italy obtained echocardiograms from 155 patients taking various Parkinson's drugs, and 90 healthy patients for a comparison group.
The study found moderate to severe valve problems in more than 23% of the patients receiving Permax compared to less than 6% of the patients in the comparison group.
The second study found that Permax users were five to seven times more likely to have leaky heart valves than patients taking other types of Parkinson's drugs, and patients taking the highest doses of Permax had a 37 times greater risk of valve damage. In this study, Dr Rene Schade and colleagues in Berlin and Montreal reviewed records from over 11,400 patients with Parkinson's disease in the UK.
"This is not a rare side effect," says Dr Bryan Roth, a pharmacology professor at the University of North Carolina, who wrote an editorial accompanying the reports in the NEJM. "That's an extraordinarily high incidence," he warns. "That makes this a serious problem."
Experts note that there are no medications that can be used to reverse valve damage and replacement surgery is the only solution.
Dr Roth published a paper several years ago warning that Permax appeared to trigger the same heart valve problems as the Fen-Phen combination of the drugs, Pondimin and Redux, which were pulled off the market in 1997, after they were linked to valve disease.
The findings of the new Permax studies could potentially represent a public health crisis. The drugs, available in generic form from a variety of producers, "have been around a long time, and a large number of people have potentially been exposed to them," said Dr Michael Okun, medical director of the National Parkinson Foundation, in the January 4, 2007 LA Times.
Permax came on the market in the US about 14 years ago, and an estimated half million people had already taken the drug by the time its maker, Eli Lilly, added valve damage to the side effects listed on the labeling in late 2003. The warning included the statement: "Some patients have required valve replacement, and deaths have been reported," but at the same time, Lilly claimed that the problem only occurred in five out of every 100,000 Permax users.
The drug is now marketed in the US by Valeant Pharmaceuticals.
Heart valve damage is an extremely serious medical condition that is both life-threatening and costly to treat. During valve replacement surgery, the breastbone is divided, the heart is stopped, and blood is sent through a heart-lung machine. Because the heart or aorta must be opened, it requires open heart surgery, according to the Texas Heart Institute.
The two kinds of valves used for replacement surgery are mechanical valves made from materials such as plastic or metal, and biological valves made from animal tissue or human tissue from a donated heart.
Mechanical valves are stronger and last longer but because blood tends to stick to them and create blood clots, patients need to take blood-thinning drugs for the rest of their lives. And because these medicines increase the risk of bleeding within the body, patients must always wear a medical alert bracelet so medical professionals will know they are taking a blood-thinning medication.
Patients with biological valves usually do not have to take blood-thinning drugs but because the valves are not as strong as mechanical valves patients may need have the valve replaced every 10 years.
Following surgery, a patient can expect to stay in the hospital for about a week, including at least 1 to 3 days in the Intensive Care Unit, the Texas Institute says. Patients with an office job, can usually go back to work in 4 to 6 weeks but those with more physically demanding jobs may need to be off work longer.
In addition to switching to another drug to treat Parkinson's disease, medical experts are advising all Permax patients to undergo testing to check for heart valve damage.
Subscribe to:
Comments (Atom)