ACE Inhibitors and Birth Defects – More Expensive and Less Effective

Evelyn Pringle November 9, 2006

About one in every four American adults has high blood pressure which is a major risk factor for heart and kidney disease, as well as stroke and heart failure, but often occurs with no warning signs.

Blood pressure is the force of blood pushing against blood vessel walls. The heart pumps blood into the arteries which carry the blood throughout the body. High blood pressure makes the heart work harder to pump blood and contributes to hardening of the arteries or atherosclerosis, according to WebMD.

Sometimes chronic hypertension or gestational hypertension leads to preeclampsia, a serious condition characterized by high blood pressure and protein in the urine, which often indicates kidney problems.

One in four pregnant women with chronic high blood pressure develops preeclampsia. In addition to increased blood pressure and protein in the urine, hand and facial swelling, sudden weight gain, persistent headaches, blurred vision, dizziness and abdominal pain, may also occur in women with the condition.

In pregnant women, high blood pressure can also decrease the blood flow to the placenta, which affects the supply of oxygen and nutrients to the fetus and increases the risk of preterm delivery.

Persistent high pressure can damage the smaller blood vessels that transport blood to and from the cells and tissues, including the tissues of the heart, lungs, brain, kidneys, liver, and the uterus.

A common class of medications used to treat high blood pressure are ACE inhibitors (angiotensin converting enzyme inhibitors). These drugs arrived on the market about 25 years ago, and they are currently the second most commonly prescribed class of drugs in the US.

The drugs act by inhibiting the production of angiotensin II, a substance that both induces constriction of blood vessels and retention of sodium, which leads to water retention, and an increased blood volume.

According to WebMD, ACE inhibitors dilate blood vessels to improve the amount of blood the heart pumps and lower blood pressure. They also help decrease the amount of work the heart has to do and protect the kidneys from the effects of hypertension and diabetes. Examples of ACE inhibitors include:

* Capoten (captopril)
* Vasotec (enalapril)
* Prinivil, Zestril (lisinopril)
* Lotensin (benazepril)
* Monopril (fosinopril)
* Altace (ramipril)
* Accupril (quinapril)
* Aceon (perindopril)
* Mavik (trandolapril)
* Univasc (moexipril)

Numerous studies have shown that ACE inhibitors can have adverse effects on the developing fetus, and for years, experts have said they should not be prescribed to pregnant women.

The most recent study documenting their harm to the fetus was conducted by researchers from Vanderbilt University, and published in the June 8, 2006, New England Journal of Medicine. The study found that fetal exposure to ACE inhibitors in the first trimester of pregnancy nearly tripled the risk of serious birth defects.

According to the research, one-third of the birth defects identified in newborns born to women who were prescribed ACE inhibitors in the first trimester, involved the heart, one-quarter involved the limbs or face, and one-tenth of the defects involved the brain or spinal cord.

In the study, the researchers examined pharmacy records and data from the Tennessee Medicaid database for the years between 1985 and 2000, which allowed them to review records of ACE inhibitors prescribed for women during the first trimester as well as infant outcomes.

In reaching their results, the researchers compared newborns exposed to ACE inhibitors with a cohort of infants whose mothers received other high blood pressure drugs in the first trimester, and a group of newborns who were not exposed to any hypertension medications.

Some experts expressed alarm at finding such serious adverse events in a study on drugs that have already been on the market for a quarter of a century. In an editorial accompanying the study in JAMA, Dr J M Friedman, MD, PhD, from the University of British Columbia in Vancouver, Canada, said more research on the teratogenic potential of ACE inhibitors in pregnancy is called for.

“This is not the last word on the subject,” he wrote, “but it is shocking to realize that it is almost the first.”

“Birth defects caused by teratogenic treatments are preventable,” Dr Friedman states, “and babies and their mothers are being harmed unnecessarily because we do not know enough about which treatments to use and which to avoid.”

“Further study is needed to determine the precise risk and its relationship to individual drugs,” he advises, “but the increase appears to be great enough to require discussion with all women of reproductive age who are prescribed ACE inhibitors.”

“Detailed fetal ultrasonography and echocardiography at about 18 weeks of gestation,” he says, “should be offered to women who have taken such drugs in the first trimester of pregnancy.”

“A woman who learns she is pregnant while taking an ACE inhibitor,” he warns, “should immediately be switched to another antihypertensive agent to minimize the risk of fetopathy.”

But the findings of this study are not actually new. A surveillance study in 2002, of Michigan Medicaid recipients involving 86 newborns exposed to captopril during the first trimester found 4 newborns (4.7%) had major birth defects, including one cardiovascular anomaly, one polydactyly, one limb reduction defect, and one hypospadias.

In addition, ACE inhibitors have long been associated with serious birth defects in infants born to mothers who used the drugs during the second and third trimester of pregnancy. Back on March 13, 1992, the FDA announced that all ACE inhibitors, “will be required to carry a “boxed warning” on the label for women in the advanced stages of pregnancy.”

“At the agency’s request,” the FDA said in a press release, “six pharmaceutical companies are simultaneously sending out a “Dear Doctor” letter emphasizing that women who take the drug in the second and third trimesters of pregnancy are running the risk of causing significant harm to fetuses, including kidney failure and face or skull deformities.”

For several years before that announcement, the labeling on ACE inhibitors had warned about the dangers of their use by pregnant women, but nonetheless, additional cases of birth defects continued to be reported. “More than 50 cases of fetal harm have been reported over the past several years,” the FDA stated.

“The warnings in the labeling,” its press release stated, “are therefore being strengthened by including a boxed warning and other changes.”

At the time, pharmacists were also alerted to the label changes and were provided stickers to paste on ACE inhibitor prescription bottles that read, “If you become pregnant consult your doctor promptly about switching to a different drug.”

Critics say that in light of all the previous studies, the use of ACE inhibitors with pregnant women should have ended long before the latest Vanderbilt study. Clearly, they say, resistance to the use of other hypertension drugs stems from the heavy promotion of ACE inhibitors to prescribing physicians.

For instance, diuretics and beta-blockers are recommended as the first-line of treatment for uncomplicated hypertension by the Joint National Commission on High Blood Pressure Treatment, yet a survey conducted on 1,700 primary care doctors, published in the December 2003, Journal of General Internal Medicine, showed that doctors believed that diuretics were less effective, and that beta-blockers had more side effects than calcium channel blockers and ACE inhibitors.

In addition, the survey found that doctors who favored prescribing the more expensive medications were more likely to pass out free drug samples provided by pharmaceutical sales representatives. Patients diagnosed with hypertension become life-long customers for Big Pharma and critics say sales reps will use whatever means necessary to lock in a new patient.

“These new, more expensive medications are being more heavily promoted by the drug companies, and one way or another that information influences how people perceive the drug’s effectiveness,” according to the Journal’s study author, Peter Ubel, MD, associate professor of internal medicine at University of Michigan Medical School.

In the hypothetical patient used in the survey, Dr Ubel says, there would be no advantage to taking ACE inhibitors over diuretics or beta-blockers. He also points out that ACE inhibitors tend to have more side effects than diuretics or beta-blockers.

Critics say there is a huge incentive for drug companies to convince doctors to prescribe ACE inhibitors instead of the more effective hypertension drugs that sell for fraction of the cost. According to IMS Health, a pharmaceutical information tracking firm, in 2005, sales of ACE inhibitors brought in more than $3.8 billion.

Chronic heart failure is a debilitating condition in which the heart’s ability to pump blood is impaired. Patients with heart failure experience a continuing decline in their health, resulting in an increased frequency of hospitalization and in premature death.

There are often no symptoms in people with hypertension. In fact, according to WebMD, nearly one-third of those who have the condition do not know it. The only way to know for certain whether hypertension is present, is to be tested.

Blood pressure is recorded as two numbers: the first, or the high number, shows the pressure during a heartbeat, and the second lower number shows the pressure between heart beats. The categories of blood pressure include:

* Normal: Less than 120/80
* Prehypertension: 120-139/80-89
* Stage 1 hypertension: 140-159/90-99
* Stage 2 hypertension: 160 and above/100 and above

An estimated 5% of pregnant women have high blood pressure before pregnancy, although many women are not diagnosed with the condition until they begin prenatal care. This is known as “essential hypertension,” but it is reportedly no different from the high blood pressure that affects many people who are overweight and inactive.

Another 5 to 8 percent of women develop high blood pressure during pregnancy, known as “gestational hypertension.” Although this condition usually goes away after delivery, gestational hypertension may increase the risk of developing chronic high blood pressure in the future.

Boston Scientific and Guidant Off to Texas Slaughterhouse

Evelyn Pringle September 6, 2006

The first, but by no means the last, Guidant trial is scheduled to begin on September 18, 2006, in Neuces County District Court in Corpus Christi, Texas before Judge Jack Hunter.

The two plaintiffs, Louis Motal, 63, and Bernice Hinojosa, 65, are surviving patients implanted with Guidant’s Ventak Prizm 2 defibrillators in 2001. The lawsuit claims that Guidant “actively concealed the … defect, suppressed reports, failed to follow through on FDA notification requirements, and failed to disclose a known defect to patients.”

“Instead of revealing the defect,” the plaintiffs allege, “defendants continued to represent their product as safe for intended use, and continued to sell the flawed [devices] despite knowing of the dangers.”

Both plaintiffs claim they suffered extreme mental anguish from knowing that the defective devices could malfunction at any time.

According to the company’s latest tally, there are about 72 class-action lawsuits and about 477 individual lawsuits filed against Guidant in various state and federal courts, Boston Scientific reported in its second quarterly report filed with the SEC. The latter number is up from about 300 cases noted in the firm’s first quarterly report filed three months earlier.

As of April 2006, Boston became the proud owner of Guidant after winning a bidding battle with Johnson and Johnson, in what will certainly not go down in history as the deal of the century.

In addition to all the lawsuit already filed, according to Boston latest SEC filing, there are more than 3,300 claims of individuals that may or may not be filed, up from 3,000 claims in the earlier report.

The lawsuits all relate to defective defibrillators and pacemakers. Defibrillators are $30,000 devices that are wired directly to the heart and send electric shocks when abnormal heart rhythms are detected and pacemakers speed up hearts that beat too slowly, and cost between $4,000 and $20,000 for each unit, according to Bloomberg News on June 26, 2006.

According to Boston report, “the majority of claimants allege no physical injury, but are suing for medical monitoring and anxiety.”

The numbers have really grown compared to Guidant’s regulatory filing with the SEC on February 22, 2006, that predicted as many as 2,500 patients may seek damages. Those claims are distinct, Guidant noted in the filing, from the claims already filed by patients in 211 individual and class action lawsuits in the US and Canada.

And the potentially bleak future of Boston does not hinge entirely on what happens in civil lawsuits. Back on February 23, 2006, the Associated Press reported that the FDA, US Department of Justice, the Securities and Exchange Commission and several state agencies are investigating Guidant over its recalls.

The company is in fact being investigated by three attorneys general on behalf of 34 states, according to the article, Litigation Mounts Over Guidant Heart Devices, in Lawyers Weekly USA, on January 30, 2006.

“In addition,” the article states, “New York State and the city of Bethlehem, Pa. are suing Guidant for reimbursement of medical costs involved in replacing the devices.”

All lawsuits pending in federal courts have been consolidated under multi-district litigation rules and moved to a US District Court in Minnesota, where Guidant has several manufacturing facilities, with the first federal trial scheduled to begin on March 15, 2007.

On June 13, 2006, the Minnesota Supreme court appointed one judge to preside over all state court cases involving lawsuits linked to last year’s Guidant product communications, Boston Scientific notes in its report.

According to Lawyers Weekly USA, the lead counsel for the Texas plaintiffs, Robert Hilliard, of Hilliard & Munoz, said documents obtained during discovery show that Guidant knew about problems with its devices as far back as April 2002, but failed to alert doctors and patients for 3 years.

“They knew they were going to kill people based on this defect,” he said.

Ted Meadows, a plaintiffs’ attorney with the Beasley Allen lawfirm in Montgomery, Alabama, who specializes in medical device litigation, told Lawyers Weekly, “There were literally tens of thousands of people who’ve had these devices implanted in them.”

“Now they’re faced with the concern,” he said, “the device might not work properly when they need it most.”

And critics say there is certainly plenty of cause for concern. On June 7, 2006, the New York Times reported that least seven patients are known to have died in episodes in which Guidant defibrillators failed to work because of the electrical defect, five involving Contak Renewals.

“But many experts believe that the number is probably higher,” the Times wrote, “because an implanted heart device is rarely examined after a patient’s death to determine if it was working properly.”

According to Mr Meadows, a key to plaintiffs’ claims will be showing that Guidant “knew or should have known there was a potential for this problem.” In addition, he said, any evidence that indicates Guidant knew about the problem and responded improperly would entitle plaintiffs to seek an award for punitive damages.

Legal experts say this evidence exists and point to a report released in March 2006, by an independent panel appointed to review the recalls that shows Guidant allowed about 4,000 potentially defective defibrillators to be implanted in patients after the company found a flaw in 2002 that caused malfunction.

“The Independent Panel believes,” the report says, “that under no circumstances should a potential or manifest risk of a preventable death be superseded by statistical analyses that indicate that performance remains with general guidelines.”

The panel also said that Guidant and other devices makers need to increase the level of data collected on device failures because studies have shown that only a relatively small number of failures are reported to the manufacturers and the FDA because doctors and hospitals do not always report problems and devices are not ordinarily inspected after a patient die.

According to Boston Scientific, the devices that may be flawed include certain Insignia and Nexus pacemakers, Contak Renewal TR/TR2 cardiac resynchronization pacemakers, and Ventak Prizm 2, Vitality and Vitality 2 implantable cardioverter defibrillators.

These products were manufactured by the company’s Cardiac Rhythm Management Group, formerly Boston Scientific/Guidant’s CRM business, and some were implanted in patients as late as between December 2005 and June 2006.

On June 7, 2006, the New York Times reported that in one analysis, Guidant engineers projected that 1 out of every 100 Contak Renewals could short-circuit, a failure rate considered high by experts.

Guidant also suspected by late 2004 that the Renewal models would become increasingly prone to failure as the devices aged, the Times said documents indicate.

The Contak Renewal combines a pacemaker and a defibrillator, often referred to as a cardiac resynchronization therapy device, or CRT-D and costs about $35,000, the Times notes.

On June 6, 2006, Texas Judge Jack Hunter, unsealed documents containing information about recalled defibrillators, saying he did not trust Guidant’s claims that they contain trade secrets. The files show that Guidant had drafted, but never sent, a “Dear Doctor” letter detailing significant potential problems with the Contak Renewal and Contak Renewal 2 model defibrillators, according to Bloomberg News on June 7, 2006.

Guidant fought hard to keep the documents confidential and for good reason obviously. The never-sent “Dear Doctor” letter disclosed the short-circuiting problem and stated that the company had “removed all non-implanted Renewal and Renewal 2CRT-Ds from hospital shelves and Guidant inventory.”

However, records reveal that by this time Guidant had already sold most of its inventory.

Earlier in 2004, the documents show that company officials drafted a memorandum for their sales representatives explaining why it was asking them to return all the unsold Contak Renewals, but the memorandum was never sent either.

Some documents provide strong evidence that Guidant weighed the risks to patients and the loss of profits and chose to place profits over the lives of patients. For instance, one company document shows that Guidant estimated it would lose about $9 million by purging its inventory of defective Contak Renewal units and parts.

Attorney Hilliard says other documents reveal that Guidant performed a risk analysis that showed there was a possibility the devices could short-circuit, and if they did, “the likelihood of death or serious injury was very likely.”

He also told Lawyers Weekly that Guidant also violated federal regulations by redesigning the devices to eliminate the flaw in 2002, without informing the FDA, and that Guidant continued selling the older devices without notifying patients of the risks.

In what experts are calling the strongest evidence to present to a jury, testimony in a 168-page deposition taken in January 2006 in the Texas case, that was made public in February 2006, has Guidant executive, Fred McCoy, acknowledging that the company made changes to one of its defibrillators in 2002, and incorrectly told the FDA that it had no effect on the product’s performance.

Mr McCoy testified that Guidant made two modifications to the Ventak Prizm 2 in 2002, to keep it from short-circuiting and that neither was approved by the FDA.

And as it turns out, only one of the changes was disclosed in the company’s annual report that year also, and Guidant said that change had no affect on the device’s performance.

In addition, in a report filed two years later, the company said that it had received FDA approval to make the changes when it had not.

Mr Hilliard told the Associated Press on February 22, 2006, that Mr McCoy’s testimony proves that Guidant sold an unapproved defibrillator in violation of federal law.

In the deposition, Mr McCoy claims that he did not learn about problems with the devices until May 2005.

More damning evidence was revealed on June 23, 2006, when the Pioneer Press reported that, “Guidant’s implantable heart devices may fail about 10 times more often than the company had projected last year, according to a U.S. Food and Drug Administration analysis released in a Texas lawsuit.”

“A judge in a product-liability lawsuit involving Guidant’s defibrillators,” the newspaper said, “recently unsealed the FDA document dated June 16, 2005.”

Back when Guidant began its recall in the summer of 2005, the firm said no more than 292 of the units were likely to break down. “But the FDA said “most” of the 16,000 recalled Contak Renewal defibrillators may have damaged insulation within five years of use,” the Press wrote, “and 40 percent of those damaged devices would fail to produce an adequate electrical shock in a medical emergency.”

At that rate, it said, at least 3,200 Renewal units would be likely to fail.

Legal experts predict that the higher projection will hurt Boston Scientific in lawsuits. “This is as damaging a document as we’re going to come across,” said Attorney Hunter Shkolnik, one of many lawyers representing patients suing Guidant, in an interview with Pioneer Press.

“It flies in the face of all the excuses Guidant has been giving for not telling patients to take these devices out immediately,” he added.

It’s difficult to imagine how things can get much worse for shareholders. In the second quarter of 2006, the company lost 27% of its value. On June 29, 2006, the Globe & Mail reported that:

“Boston Scientific, which laid out $27.5-billion in cash and shares for Guidant, has bought itself what, so far, looks like a massive and costly series of headaches, in the form of product recalls and lawsuits. These have helped drive its stock price to a four-year low of less than $17 on the New York Stock Exchange, down more than $9 from early January.”

However, critics say Boston Scientific also has its laundry list of problems. According to the Globe, before it acquired Guidant, both Boston and its target, received corporate warning letters from the FDA saying that, until they have demonstrably improved their quality control, the agency will not approve new products for sale in the US.

Roche Puts Accutane Profits Over Lives of Consumers

Evelyn Pringle August 31, 2006

In 1985, Accutane’s package insert directed at doctors first mentioned reports of depression in patients taking the acne drug, which means that more than 20 years ago, Hoffman-LaRoche at least suspected there might be a risk of depression and suicide by persons taking the drug.

However, Roche’s financial records show that the company is not about to let a little thing like the death of its customers get in the way of corporate profits, because the drug is still a best seller and young people with no history of depression who take it are still killing themselves.

On November 14, 2004, BBC News reported that Jon Medland, 22, in the final year of medical school at Manchester University, hanged himself at his student lodgings on January 13, 2004 while on Accutane.

When questioned about the incident, Roche told BBC News that the drug carried a warning of possible mood changes and depression, but said “no causal link had been established between the drug and either depression or suicide.”

Less than a year later, in September 2005, BBC News reported that David Roberts, 21, had been on the drug for two months when he hanged himself near his Liverpool home.

And once again, according to BBC News, “Roche insists there is no proven relationship between the drug and depression.”

However, David’s father, Fred Roberts, said he could think of no other explanation for the tragedy. “David was the most happy-go-lucky, carefree lad you could ever hope to meet. He had plenty of friends, he enjoyed going out, he had a happy family life.”

“His acne wasn’t severe at all. He had a few spots and, like any young person, he wanted to get rid of them.”

“The change in him was so sudden,” Mr Roberts said, “there’s no other reason for it than the effect of this drug.”

On January 15, 2006, 15-year-old Justin Zimmer, of Menasha, Wisconsin, shot himself and his parents blame Accutane.

Justin’s parents and a friend told the Appleton Post Crescent on July 18, 2006, that he gave no indication that he was depressed and that he was all excited about getting his driver’s license in a couple of weeks.

Roche’s comments to the BBC are clearly dishonest considering that in 1986, doctors were notified that Accutane users who became depressed saw their depression lift when they stopped taking the drug but return when they were placed back on the medication. Doctors were also informed that simply stopping Accutane therapy might not be sufficient to treat the depression and that follow up on the depression might be necessary.

In 1998, the FDA notified doctors that Accutane, “may cause depression, psychosis, and rarely, suicidal ideation, suicide attempts and suicide.”

The agency issued a MedWatch alert in February 1998, that said due to the adverse event reports received, the FDA felt there was sufficient cause to strengthen the warning on the Accutane label to include the risk of psychosis and suicidal thoughts and actions.

The February 23, 1998, FDA Memorandum, “Isotretinoin and Depression: Spontaneous Report Data,” listed 31 cases of suicide, suicide attempt or suicide ideation associated with Accutane. Of those cases, 12 were suicides, 9 were male, 2 were female, and 1 unknown, and the average age was 17. The event occurred on average, 88 days after the patient started taking the drug.

The FDA acknowledged in the memorandum that for “the majority, there was no antecedent history of depression and the patients were not noted or known to be depressed in the time period prior to their suicide.”

During a US House Oversight and Investigation Subcommittee hearing on the Safety Issues Relating to Accutane, on December 11, 2002, internal documents from the nation’s regulatory agencies were entered into the record that revealed that public health officials had been voicing concerns about patients committing suicide while on Accutane for well over a decade.

For instance, a 1998 memo from the FDA’s medical officer in charge of Accutane states: “Given all the pieces of evidence available, it is difficult to avoid the conclusion that Accutane can adversely affect the adult human brain in clinically significant ways and that Accutane use is associated with severe psychiatric disease in some patients.”

The memo recommends “active consideration of removal of Accutane from the market.”

But instead of removing the drug from the market, on February 25, 1998, the FDA required Roche to add the following bold-face warning to drug’s physician package insert:

“WARNINGS – Psychiatric Disorders: Accutane may cause depression, psychosis and, rarely, suicidal ideation, suicide attempts and suicide. Discontinuation of Accutane therapy may be insufficient; further evaluation may be necessary. No mechanism of action has been established for these events.”

“ADVERSE REACTIONS – In the postmarketing period, a number of patients treated with Accutane have reported depression, psychosis and rarely, suicidal, ideation, suicide attempts and suicide. Of the patients reporting depression, some reported that the depression subsided with discontinuation of therapy and recurred with reinstitution of therapy.”

In perverse twist of logic, in the same year, Roche began actively marketing Accutane as a treatment for depression, under the theory that it could help people who were suffering from depression due to poor self-image as a result of acne.

On March 5, 1998, Roche received a letter from the FDA stating that such promotion was false and misleading, and that Accutane had never been approved for the treatment of depression, and that in fact, just the opposite was true. The letter stated in relevant part:

“Roche … has not systematically studied the ability of Accutane to modify or prevent such illnesses as depression and has presented no basis for asserting that Accutane is effective in improving the psychosocial and emotional well-being of such patients.

“This claim is particularly troublesome in light of information recently presented in a Dear Doctor letter, that Accutane may cause depression, psychosis, and rarely, suicidal ideation, suicide attempts and suicide.”

The FDA also instructed Roche to “prominently disclose information about the psychiatric disorders described in the warnings section of the revised labeling” in Accutane advertisements.

In September 1998, the FDA presented an Advisory Panel with 37 cases of suicide attributed to Accutane since 1983. However, the number was later changed to 44 suicides after Roche corrected its calculations.

The Adverse Event Reporting System (AERS) is a computerized database of post-marketing adverse events, designed to support the FDA’s post-marketing surveillance program of all approved drugs.

The reports in AERS are evaluated by agency reviewers in the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER) to detect safety signals and to monitor drug safety.

The results of a review of AERS by congressional staffers working on behalf of Congressman, Bart Stupak (D-MI), revealed during an October 5, 2000, hearing, reported 54 more suicides by persons on Accutane after the FDA issued its MedWatch in 1998.

In 2004, the Alliance for Human Research Protection, asked Keith Altman, an Adverse Drug Reaction Statistics Analyst, to analyze the FDA’s Medwatch database for drug-linked suicides by children under the age of 18. The analysis found that between 1989 and June 2003, there were 216 reports of drug-linked suicides, and 72 were associated with Accutane.

The Alliance points out that MedWatch reflects approximately 1% of actual adverse events, so 72 Accutane suicide reports could represent as many as 7,200 suicides.

Congressman Bart Stupak, lost his son, BJ, to suicide on Mother’s Day, May 14, 2000, at the age of 17, from a self-inflicted gunshot wound and BJ was on Accutane at the time of his death.

On December 11, 2002, Rep Stupak told the audience at the Safety Issues Surrounding Accutane Hearing that, “Anyone who knew BJ could not understand why a young man with such an outgoing personality and bright future would end his own life.”

“BJ taking his own life,” Rep Stupak said, “is contrary to everything he believed in!”

After his suicide, BJ’s mother, Laurie, checked out Accutane on the Internet and found many adverse events associated with the drug that they was never told about.

But the most disturbing find she said, was the February 1998 MedWatch stating, “The FDA is advising consumers and health care providers of new safety information regarding the prescription anti-acne drug Accutane (isotretinoin) and isolated reports of depression, psychosis, and rarely suicidal thoughts and actions.”

“After we found the MedWatch,” Rep Stupak said, “I wondered why the FDA put out this warning, 18 years after the drug was approved?”

“More important,” he continued, “why weren’t these warnings on BJ’s Accutane package which had been revised 4 months after the MedWatch was issued?”

Two other couples testified at the hearing about their sons who had no history of depression, but yet committed suicide while taking Accutane. The spontaneity of the suicides became the center piece of discussion between committee members and witnesses during the hearing.

Susan and Martin Turney from Watertown, New York testified about their 16-year-old son, Matthew, who took his own life on March 14, 2001, and was on Accutane at the time of his death.

In retracing the days leading up to Matt’s death, nothing indicated that anything was wrong. The night before the suicide, everything was normal his parents recalled. The family had a nice dinner together, talked about the day’s events and joked and laughed with each other like always.

The next morning, Matt got up for school as usual. Before leaving to catch the bus, he looked at his father, smiled and said “Good Bye,” and yelled, “Good Bye Mom. I love you,” to his mother who was in another room, just like he did every morning.

By all accounts, Matt was fine at school that day. He talked to his guidance counselor about a program she had recommended for the next year. He asked a girl to a dance and she agreed to go. He took a couple of tests and did well.

On the bus ride home, Matt sat with his friends and laughed and fooled around just like any other day. He got off the bus and stopped to pick up the newspaper and mail as usual. He took off his shoes in the entryway, placed the mail and newspaper on the kitchen counter as he always did, and went into his room and hung up his coat.

His parents say it is at this point that Matt’s normal routine changed. He did not turn on the TV, or get a snack or check his email as usual. Instead, he apparently went into the master bedroom, unlocked the gun case, took out a gun and shot himself.

His father came home from work and yelled “Hello” to Matt, but got no response so he went looking for him and found Matt on the floor of the bedroom with no heartbeat.

While answering questions from police at the hospital, Matt’s parents were asked if Matt was taking any medication and they said Accutane. As soon as they answered, they remembered a TV Dateline program about the parents whose son committed suicide while on Accutane.

After watching the program Matt and his mother had went to the Dermatologist to discuss the story and their concerns about Accutane. The Dermatologist said that there had been a couple of unsubstantiated cases of depression and suicide, but that there was no scientific proof that Accutane could cause it and that Matt “didn’t fit the profile anyway.”

Matt’s parents told the committee how they later found out that Accutane was supposed to be reserved for the most severe cases of nodular, cystic acne and provided the panel with a school picture of their son taken about 2 weeks before he started on Accutane that showed he did not have a severe acne problem.

“After talking to all of Matt’s friends, family, teachers, and co-workers,” his father told the committee, “we confirmed what we had already known, Matthew was not depressed!”

“His sudden death came as a shock to every person who knew Matt, including us, his parents,” he said. Matt’s suicide was “spontaneous,” his parents said:

“There was no depression. There was no warning. There was nothing for us to look for. There was no reason for his death, other than Accutane.”

Michael and Caroline Bencz also testified at the hearing about how their son, James, committed suicide without any sign that he was depressed or troubled. They told the panel that at the time of his death, he had everything to live for stating:

“James was not the person anyone would expect to commit suicide. He had friends and family. He had financial and personal success. He had plans for the future – both near and long term.

“The week James died, he was to leave on a skiing trip to Austria with a few of his firefighter buddies. James had plans for his future, and death was not in that plan.”

“He was witty, humorous, talented, a great sportsman, intelligent, and highly competitive,” his parent said, “but most of all, above all that, a wonderful human being.

In late 2001, they told the panel, they learned that a doctor prescribed Accutane for James. These parents also provided the committee with a picture of their to show that he never had a severe acne problem. All they could figure out was that maybe the skin diving suit he wore may have irritated his skin on his neck and back.

The last day they heard from James, on February 23, 2002, he called to say he did not feel well, that he had a headache. His last words to his parents were: “I don’t feel too good, I’m going to try to get some sleep.”

Over the next few days they did not hear from James which was very unusual. It was not like him, his parents said, to disappear for days at a time without letting anyone know where he was.

When he did not turn up, a massive man hunt was conducted, and he was eventually found on March 4, 2002, at the bottom of a lake, with a 44 pound barbell strapped to his body. A lake where James and his sister used to sit as children skipping rocks.

He died, his father told the committee, “under circumstances so bizarre for someone like James – a diver, a firefighter, and an athlete – with so much to live for, and so many future plans.”

“We wish every minute of every day that we had never heard of that drug,” they told the committee. “It took our son, our life as we know it, and left us with huge craters in our hearts that can never be filled in again.”

These reports of inexplicable suicides were alarming to members of the committee. “Is it possible that this medication has an effect, an action that results in spontaneous, impulsive, self destructive behavior that is different from that which occurs from a clinical depression?,” Congressman Ted Strickland (D-OH), who has a PhD in psychology, asked.

“I know of no clinical concept of depression that has an instantaneous onset and what we’ve heard described are people who are emotionally,” Rep Strickland said, “psychologically healthy with none of the clinical signs of depression spontaneously doing something to themselves.”

“So I’m wondering,” he concluded, “if we are dealing here with something other than depression, and that we ought to recognize that.”

The FDA Office of Drug Safety keeps a monthly cumulative count of psychiatric adverse event reports in AERS. According to Dr Janet Woodcock, Director of the Center for Drug Evaluation and Research, at the hearing, as of November 30, 2002, AERS contained 3,104 reports with at least one reported psychiatric event.

The FDA is aware of 173 reports of suicide in association with Accutane, she told the panel. She noted that the FDA had requested quarterly summaries of psychiatric events from Roche and said the most recent summary through August 2002 indicated approximately 6,000 additional reports that include psychiatric events

Because the 173 cases of suicides ware based on self reporting, experts say that figure is highly suspect and that being as few as 1% of suicides are reported as adverse events, it could mean that the actual number of suicides may be as high as 17,000.

During his December 11, 2002 statement to the committee, Congressman Stupak pointed the finger of blame directly at the FDA when stating:

“Accutane is a powerful, dangerous drug with devastating consequences for some patients. The birth defects caused by Accutane are horrific. The FDA’s response to the birth defects and psychiatric events has been inadequate, irresponsible and unacceptable. Thousands of babies, teenagers, and young adults have died prematurely.

“While the FDA has been aware of the birth defects since at least 1982 and the psychiatric injuries since 1985, their responsibility to protect the public has been inconsistent and without direction.”

There is no debate about whether Accutane is a moneymaker. According to the Associated Press on August 21, 2006, patients usually take it for up to a year at a cost of $10 to $15 per day. And in the December 11, 2002 hearing, Congressman Stupak turned the attention of the committee to Roche’s conduct of putting profits before people and stated:

“They have done everything possible to prevent the American people from learning of the psychiatric injuries and deaths associated with Accutane. Even, today … Roche will deny any casual effect of Accutane with the abortions, deaths, and suicides caused by their product.”

“We cannot allow the drug manufacturer and the FDA to continue to turn a blind eye to the lives lost, families devastated and dreams dashed by an acne drug,” he said.

“The American people, our children,” he said, “are not collateral damage in the scheme of corporate profits!”

Big Pharma Bankrupting US Health Care System

Evelyn Pringle August 29, 2006

Big Pharma is bankrupting the nation’s health care system by convincing prescribing doctors to over-medicate patients with expensive psychiatric drugs and then send the bills to government programs like Medicaid and Medicare.

The peddling of the new generation of psychiatric drugs that include the selective serotonin reuptake inhibitors antidepressants (SSRIs), and atypical antipsychotics that began arriving on the market in the late 1980s, has become a cottage industry in the US.

Between 1986 and 2004, the sale of antidepressants went from $240 million to $11.2 billion and the sale of antipsychotic drugs rose from $263 million in 1986 to $8.6 billion in 2004.

These two classes of drugs combined went from $500 million to nearly $20 billion in 2004, which translates to a 40-fold increase, according to award winning journalist, Robert Whitaker, author of Mad In America.

A University of Georgia study published in the June 2006 issue of Journal of Clinical Psychiatry, found that three-quarters of people prescribed antidepressant drugs receive the medications for a reason not approved by the federal FDA.

The researchers reviewed records on drugs prescribed to 107,000 Georgia Medicaid recipients in 2001. The researchers used Medicaid data because it is comprehensive and easily accessible, and said the results are likely to be comparable in other states.

The study examined rates of off-label prescribing for drugs that act on the central nervous system and found that 75% of antidepressant recipients and 64% of antipsychotic recipients these received the drugs off-label.

While study authors Dr Hua Chen and Professor Jack Fincham acknowledged that there are legitimate uses for off-label prescribing, they said that in many cases doctors write off-label prescriptions based on limited or anecdotal evidence.

“Most off-label drug mentions have little or no scientific support,” said study co-author Jack Fincham, Professor of Pharmacy Care at the University of Georgia College of Pharmacy to Doctor’s Guide News on July 25, 2006. “And when I say most,” he said, “it’s like 70% to 75%.”

“Many patients,” he noted, “have no idea that this goes on and just assume that the physician is writing a prescription for their indication.”

“Physicians have the right to prescribe any medication off label,” Dr Chen said, “but they also have the responsibility to inform patients that this medication is being used off label.”

Study leader, Dr Chen, an assistant professor at the University of Houston, said the findings reveal a significant gap in the nation’s drug safety system. The FDA approval process is widely regarded as the world’s most rigorous, she noted, but said off-label prescribing regularly exposes consumers to drugs that are untested for their condition.

“There’s a big gap between this very strict approval process and this very liberal utilization practice,” Chen said. “Something must be done to fill this gap.”

Professor Fincham, author of the book, “Taking Your Medicine: A Guide to Medication Regimens and Compliance for Patients and Caregivers,” told Doctor’s Guide that considering the aging population and the increasing likelihood of off-label prescribing with age, the number of people receiving off-label drugs will likely increase in the coming years.

According to Dr Chen and Professor Fincham, the off-label use of central nervous system drugs can account from anywhere from 25% to 80% of a drug’s annual sales.

Drug makers have found ways to influence prescribers who tend to the elderly in nursing homes to funnel Medicare funds to Big Pharma through senior citizens. In one 2003 study published in the Archives of Internal Medicine, researchers found that 75% of long-term care elderly residents were receiving psychotropic medications.

Another study published in the August 2004 Archives of Internal Medicine, noted that 41% of prescriptions, for 765,423 people over age 65, were for psychotropic medications.

A more recent June 13, 2005, study in the Archives examined the quality of antipsychotic prescriptions in nursing home for approximately 2.5 million Medicaid beneficiaries and found that “over half (58.2%),” received drugs that exceeded the maximum recommended dosage, received duplicate therapy, or under the guidelines, had inappropriate conditions for the medications to begin with. The study determined that more than 200,000 residents received antipsychotic therapy but had “no appropriate indications for use.”

On April 11, 2005, the FDA may have plugged a hole in the dike for the river of Medicare funding flowing from the nursing home industry when it announced that elderly patients with dementia who were given antipsychotic drugs were far more likely to die prematurely than those given placebos and also announced the addition of black box warnings about the increased risk of death on the labels of Zyprexa (Eli Lilly) Risperdal (Johnson & Johnson) Abilify (Bristol-Myers Squibb), Clozril (Novartis), and Geodon (Pfizer).

On May 1, 2006, the London Free Press reported a study by Toronto’s Institute for Clinical Evaluative Sciences that showed seniors who were prescribed the new SSRIs such as Prozac, Paxil and Zoloft were nearly 5 times more likely to commit suicide during the first month on the drugs than those patients given the older class of medications used to treat depression.

In conducting the study, the researchers used Ontario coroners’ reports, prescription records and hospital data, and identified 1,142 suicides among older Ontarians, 66 and up, from 1992 to 2000, and determined whether they had been prescribed antidepressants in the 6 months before their deaths.

Among those patients who were, the risk of suicide in the first month for those taking an SSRI was nearly 5 times higher than for patients on the older antidepressants, such as Elavil.

The study also found that SSRIs were associated with more violent means of committing suicide, such as the use of firearms, or jumping from heights and hanging, Dr David Juurlink, the study’s lead author told the London Free Press.

While studies have found an increased risk of suicidal thoughts and behaviors among children taking SSRIs, up until now, little research has been done on their link to suicide in aging patients.

Big Pharma has found ways to influence doctors within the Veteran Administration’s hospital system to convince them to prescribe the new expensive psychiatric drugs rather than the older, cheaper and equally effective medications.

Dr Robert Rosenheck, a Director with the Department of Veterans Affairs, reviewed the prescribing records for schizophrenic patients in the VA system and found that more than 80% are now on the new antipsychotics.

In 2003, he calculated that the VA spent more than $208 million on antipsychotic drugs, with over $106 million going for Zyprexa alone.

A government funded study conducted by the National Institute of Mental Health compared four new generation antipsychotics against an older medication, perphenazine and only one, Zyprexa, worked any better at all, and then the difference was minimal.

However, Zyprexa also carried the most serious risk of side effects and was found to be far more likely to cause severe weight gain and diabetes than the other drugs. The NIMH study also determined that over 18 months, nearly 75% of the patients had quit taking their assigned drugs, signaling a high level of dissatisfaction with the medications.

According to the November 24, 2005, Providence Journal, the four new antiphychotics studied soak up about $10 billion a year, depending on the dosage, and can cost up to 10 times more than the older generic and the Medicaid population alone spends an estimated $3 billion a year for these antipsychotic medications.

Big Pharma has known that the new antipsychotics were ineffective for years. A review of 52 studies involving 12,649 patients published in the December 2000 British Journal of Psychiatry reported: “There is no clear evidence that the atypical antipsychotics are more effective or better tolerated than conventional antipsychotics.”

In 2003, an outright bribery scheme was discovered at a hospital in Massachusetts where doctors were found to have changed the medication of 4 patients for non-medical reasons. The November 10, 2003, Boston Globe, reported that the patients were switched to Risperdal, without consent or medical necessity, to make them eligible for a clinical trial sponsored by Janssen Pharmaceuticals.

After uninvolved staff members complained, the situation was investigated and the trial was stopped. As a result, all state hospital doctors were required to undergo re-certification in the ethics of medical research and the hospital’s director, Dr Douglas Hughes, resigned after it was revealed that in the same year, he had received $30,000 in speaker’s fees from Janssen.

In recent years the nation’s children have become a major target for the pharmaceutical industry. The new antipsychotics are not approved to treat any condition in children but studies of children in Medicaid programs and HMOs have found a drastic increase in the use of the drugs with children, particularly for behavioral disorders, according to research published in the March/April 2006 Journal of Ambulatory Pediatrics.

Researchers lead by Dr William Cooper at Vanderbilt University in Nashville, TN, evaluated data drawn from the National Ambulatory Medical Care Survey and the National Hospital Ambulatory Medical Care Survey, which are national samples of health care services rendered to the US population and conducted by the National Center for Health Statistics.

Between 1995-2002, the study found that there were 5,762,193 outpatient visits to health care providers by children between the ages of 2-18 years-old, during which an antipsychotic was prescribed.

The study shows that Big Pharma has doctors in every setting prescribing these drugs to kids. Nearly 80% of the visits occurred in physician’s offices, 14% in outpatient clinics, and 9% occurred in emergency departments. According to the study, 32% of the nearly 6 million prescriptions were written during visits to pediatricians, family physicians, emergency department physicians, or other types of providers.

According to Doctor Cooper, these antipsychotic medications have been studied in only a few controlled trials in children, and have not been studied at all for many behavioral diagnoses. But yet, the most common diagnosis for children prescribed an antipsychotic was attention deficit hyperactivity disorder or conduct disorder, accounting for 29.0% of all antipsychotic visits.

Affective disorders such as bipolar disorder or depression accounted for 23.6% of the visits so that together, behavioral and affective disorders represented more than half of the prescriptions during the study period. According to the authors, there is no evidence from controlled studies that supports the use of antipsychotics for behavioral conditions.

The report states that over 50% of the prescriptions were for a diagnosis for which antipsychotics have not been studied in children and that there is little recognized benefits to these medications in many of the children receiving them.

“Thus,” the report notes, “the increasing prescribing of antipsychotic medications in children for behavioral indications is concerning given the paucity of information on the overall benefits and risks of this class of medications in children.”

A finding in the study that demonstrates the ability of Big Pharma to successfully market drugs off-label to children is that the increased prescribing of antipsychotics for behavioral disorders coincided with the introduction of new atypical antipsychotic medications.

The study also explained that there has been no increase in mental health disorders such as schizophrenia that would account for the increases “as recent studies do not suggest significant increases in the incidence of schizophrenia,” it concluded.

“In addition,” the researchers explained, “schizophrenia and psychosis accounted for only 13.5% of the total antipsychotic visits during the study period, so this diagnosis alone could not explain the increase.”

“Therefore, the most likely explanation for the study results is that similar to our findings in the Tennessee Medicaid population,” the authors said, “there was a substantial increase in physician prescribing of antipsychotics during the study period.”

The mass drugging of children on Medicaid is happening all over the country. In 2001, psychiatrist, Dr Stefan Kruszewski, was hired to review psychiatric care provided by government-funded agencies in Pennsylvania to identify fraud, waste, and abuse, and found cases of what he refers to as “insane polypharmacy,” where children were placed in state-run treatment facilities and over-medicated with the new antipsychotics and anticonvulsants sometimes for years.

Over the past decade since the new antipsychotics came on the market, they have been linked to serious side effects, that include the risk of substantial weight gain, diabetes, and cardiac dysrythmias, and according to Dr Copper’s report, preliminary studies suggest that side effects may occur more commonly and be more severe in children than in adults.

This assertion is proving to be true. The Children’s Hospital of Philadelphia recently found that 19% of newly diagnosed Type 2 diabetic children were being treated with the new antipsychotic drugs, all of which are now required to carry a black box warning to alert doctors about the dangers of diabetes associated with the drugs.

A recent analysis by USA TODAY of the FDA adverse event reporting system between 2000 and 2004, found at least 45 deaths of children where the “primary suspect” was an atypical antipsychotic. USA also discovered more than 1,300 cases of serious side effects, including some that were life threatening, such as convulsions and a low white blood cell count.

However, critics of regulatory officials are quick to point out that the FDA has known about the dangers of these drugs long before now. For instance, in the fall of 2001, a paper published in the Journal of Clinical Psychiatry said the FDA had been alerted to 19 cases of diabetes associated with Zyprexa and one patient died.

Of the 19 patients, the paper said, seven had newly diagnosed hyperglycemia and in 2 cases, the sugar disorder developed within one week of taking Zyprexa, and developed within six months for the other 8 patients.

The most studied adverse effect has been their association with hyperglycemia, in some cases leading to ketoacidosis, coma, or death. But nonetheless, even though Risperdal was recently refused FDA approval for treating autism, this class of drugs are increasingly being used off-label to treat behavior problems in children on the autism spectrum.

As for treating children who are diagnosed with schizophrenia, the results of a study published in August 2006, by the New York Psychiatric Institute found that the older antipsychotics work much better than the new. The average response rate in children to medication among 8 studies employing the new antipsychotics was 55.7%, compared to a 72.3% response rate among children in 13 studies employing older drugs.

The study also found that the average weight gain in patients treated with the older drugs was much lowers and the sedation side effect was more common with the new drugs. The authors noted that the FDA “has not approved any antipsychotic drugs for treating childhood schizophrenia; yet, clinicians routinely use medications for this disorder.”

However, there are signs that Big Pharma’s ability to use children as funnels to drain tax dollars from government health care programs might be waning. On August 16, 2006, the Houston Chronicle reported that 5 doctors who treat poor children in Texas were notified that they need to return Medicaid money used to pay for psychiatric drugs to that state.

This latest move, newspaper said, is part of a 2-year effort to better regulate how children on Medicaid are prescribed psychiatric drugs.

Two years ago, Brian Flood, the Texas Health and Human Services’ Inspector General, and Texas Comptroller Carole Keeton Strayhorn, began reviewing information on how doctors were prescribing stimulants, antidepressants and antipsychotics to children on Medicaid.

The studies revealed that children were being prescribed multiple psychiatric drugs and some children as young as 3 were taking the mood-altering medications.

Ms Strayhorn’s study found a case where one child had 14 prescriptions for 11 different medications, at a cost of $1,088 a month.

Mr Flood’s review of a two-month period of Medicaid records determined that 63,118 children were on stimulants, antidepressants or antipsychotics, with nearly one-third of the kids taking drugs from more than one of the 3 classes of drugs at the same time.

The review of records found that doctors had filed 114,315 claims amounting to more than $17 million for the children.

As a result of the studies, last year, the Texas Health and Human Services Commission established strict guidelines for prescribing psychiatric drugs for children on Medicaid and the state has seen a dramatic reduction in multiple prescriptions.

The really good news is that a great number of Texas children are apparently cured of their mental illnesses because an analysis of the data taken last year shows that within 5 months after the new rules were in place, the number of foster care children prescribed five or more psychiatric drugs fell by 31%.

There are about 1.9 million Texas children on Medicaid, according to the Chronicle.

Many states are going after the drug makers to retrieve the money spent on illegal off-label prescriptions. In July, 2006, Mississippi filed a lawsuit against Eli Lilly with allegations that the company improperly marketed Zyprexa for “off-label” uses and defrauded the state Medicaid program out of millions of dollars, according to the July 27, 2006, Jackson Clarion Ledger.

The lawsuit alleges that Lilly sales representatives convinced Mississippi doctors to prescribe the Zyprexa to patients who suffered from anxiety, mood swings and disturbed sleep when the drug was only FDA approved for the treatment of adults with bipolar disorder or schizophrenia.

The suit also alleges that Lilly did not properly emphasize the dangers of the drug, such as an increased risk of diabetes, and that treating Medicaid patients who became ill from the drug has increased Medicaid costs.

Experts in the medical profession who have not been compromised by the drug companies are furious over the practice of drugging kids with dangerous psychiatric drugs for profit.

For instance, Pediatrician, Dr Lawrence Diller, author of the book, “Should I Medicate My Child,” testified before an FDA advisory committee in September 2004, on the rampant off-label prescribing of SSRI drugs to children after learning about 8 previously undisclosed studies that proved the drug makers knew all the long that SSRIs were linked to suicide in children but kept the findings hidden from doctors who were prescribing the drugs.

Dr Diller said the “final blow” was learning of these 8 studies and that the loss of credibility within the medical profession extended beyond psychiatry into all of medicine and ended his testimony by stating:

“The blame is clear: The money, power and influence of the pharmaceutical industry corrupt all. The pervasive control that the drug companies have over medial research, publications, professional organizations, doctors’ practices, Congress, and yes, even agencies like the FDA, is the American equivalent of a drug cartel.”

Accutane still a Top Seller for Hoffman-LaRoche

Evelyn Pringle August 25, 2006

Accutane, manufactured by Hoffman-LaRoche, was FDA approved in 1982, only to treat the most severe form of acne. Yet by 1998, the medication was the company’s second-largest-selling drug, with about $800 million in sales.

Accutane (Isotretinoin) entered the market in the US in 1982, and has been at the center of one firestorm after another ever since. It was never intended to treat a large number of patients. The FDA approved the drug for the treatment of severe nodular cystic acne, a type of acne that is painful, disfiguring, and will not respond to other forms of treatment.

The FDA approved labeling specifically points out that the drug is not to be considered a treatment of first choice:

“Because of significant adverse effects associated with its use, Accutane should be reserved for patients with severe nodular acne who are unresponsive to conventional therapy, including systemic antibiotics.”

The original labeling issued in 1982, designated the drug as Category X, meaning it was to be avoided by all pregnant women. Yet by 1983, babies were being born with birth defects to mothers who used the drug during pregnancy.

Alarmed by these reports, in September 1983, the non-profit consumer advocacy group, Public Citizen, submitted a petition to the FDA requesting patient package inserts and a black box warning label be added to Accutane describing the risk of birth defects and mental retardation.

Looking back, Public Citizen has been warning the FDA about the risks of serious harm to fetuses exposed to Accutane for more than 20 years. In 1984 the group sent a letter to the FDA advocating for improved pregnancy surveillance and lower dosing regimens.

During an FDA Advisory Committee meeting in 1988, the group described isotretinoin as an imminent public health hazard and urged the panel to remove the drug from the market unless tighter and effective restrictions were implemented.

The next year the group testified again and asked the FDA to withdraw isotretinoin from the market unless the previously proposed restrictions were adopted immediately.

In 1989, the CDC testified before an FDA Advisory Committee, and stated that the birth of babies with defects caused by fetal exposure to Accutane was unnecessary and called the FDA’s decision to allow the marketing of Accutane, a “failed regulatory experiment.”

At a December 11, 2002 House Oversight and Investigation Subcommittee hearing on the Safety Issues Relating to Accutane, internal documents from the nation’s regulatory agencies were placed in the record that showed public health officials had been expressing serious concerns about Accutane and birth defects for well over a decade.

For instance, a 1990 internal FDA memo stated, “Accutane poses an imminent hazard to public health, and as such should be withdrawn immediately from the market.”

A 1990 report by the FDA said, “The magnitude of fetal injury and death has been great and permanent, with 11,000 to 13,000 Accutane-related abortions and 900 to 1,100 Accutane birth defects.”

In August 1997, the FDA issued a warning letter to Roche for failing to submit serious adverse event reports in a timely manner and Roche claimed its computer systems were responsible for delays of up to eight years in complying with the law.

A February 1998 FDA memo stated that Roche “had not acted in good faith to truly and accurately answer questions relating to Accutane use in women and pregnancy exposure.”

The memo goes on to recommend “active consideration of removal of Accutane from the market.”

A 1998 letter to the FDA from an official at the Centers For Disease Control compared Accutane to the infamous cancer and leprosy drug, Thalidomide, known for causing of birth defects, and stated, “we simply need to remove the drug from the market.”

In response to calls for the withdrawal of Accutane, Roche proposed a patient education program on the risk of birth defects, that included patient materials and informed consent forms for women to sign before receiving the drug.

In September, 2000, because the number of prescriptions to women of child-bearing age had tripled from 70,000 a year in 1989, to almost 210,000 in 1999, there was more concern over the increasing number of pregnant women exposed to the drug so FDA’s Dermatologic and Ophthalmic Drugs Advisory Committee held a meeting to discuss what measures might help prevent further fetal exposure.

Public Citizen once again testified at the hearing and recommended that a Patient Medication Guide be issued and again urged the FDA to remove Accutane from the market unless restrictions were implemented and proven to be effective.

As a result of recommendations made by the Advisory Committee following the hearing, Roche agreed to develop a program designed to prevent pregnancies in women using Accutane.

The “System to Manage Accutane Related Teratogenicity,” or SMART program, was implemented in April 2002, and required women to have 2 pregnancy tests before starting on Accutane, to get a pregnancy test each month before refilling a prescription, to receive counseling on birth control, and to agree to use two forms of birth control simultaneously while using Accutane.

The Adverse Event Reporting System (AERS) is a computerized database of post-marketing adverse events for all approved drugs, designed to support the FDA’s post-marketing safety surveillance program.

The reports in AERS are evaluated by agency reviewers in the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER) to detect safety signals and to monitor drug safety.

During the December 11, 2002 hearing, Roche claimed that only 2,300 pregnancies had occurred among Accutane users since its introduction in 1982. However, Congressman Bart Stupak (D-MI), refuted that assertion, by citing a 1999 company report indicating that in a single 3 month period that year, 93 unwanted pregnancies were reported and 42 abortions occurred.

According to Dr Janet Woodcock, Director of the CDER at the hearing, AERS contained almost 23,000 adverse event reports for Accutane from the time of its approval in 1982 to December 2002.

For 2002 thus far, she said, AERS contains just over 1,100 adverse event reports. During 2002, she told the panel, the five most frequently reported reactions are, in descending order, depression, pregnancy, induced abortion, suicidal ideation, and headache.

Dr Woodcock explained that the Office of Drug Safety (ODS) within CDER maintains a quarterly cumulative count of reports of Accutane-exposed pregnancies and outcome, if known, based on Roche’s quarterly submission.

The latest update as of June 2002, she said, “shows a total of 2,350 Accutane-exposed pregnancies and 172 babies born with a congenital defect or anomaly in the U.S. since the product was approved in 1982.”

According to testimony by Dr Nancy Green, medical director of the March of Dimes Birth Defects Foundation, Associate Professor of Pediatrics and Cell Biology at the Albert Einstein College of Medicine, the major birth defects include a syndrome that includes mental retardation, hydrocephalus, microcephaly, cleft lip and palate, cardiovascular anomalies, and ear and limb abnormalities.

Lynn Martinez, Manager of the Organization of Teratology Information Services (OTIS), a national group that tracks prenatal birth defects exposure, informed the committee that OTIS was still receiving reports from women who had become pregnant while taking Accutane, despite the SMART program.

To measure compliance with the SMART program, researchers surveyed 34 women who had called a member service of the OTIS between April 2002 and September 2004 because they had become pregnant while taking isotretinoin.

The survey revealed that only 24% of the women received contraception counseling and while SMART required women to use two forms of birth control simultaneously while taking Accutane, only 62% of the women reported using any birth control and only 29% of those women reported using two forms.

According to the rules, women were required to have two negative pregnancy tests before receiving a prescription, but 76% said they did not have a second pregnancy test

When asked about the requirement of receiving a pregnancy test each month before refilling a prescription, 35% of the women surveyed said they did not have monthly pregnancy tests.

In addition, only 53% of the women reported signing the informed consent required by SMART prior to taking the drug.

Julia Robertson, coordinator of the Birth Defects and Genetics Program at the Utah Department of Health in Salt Lake City, and lead author of the study, said the failure to avoid pregnancy had resulted in a high rate of abortions and at least one baby born with severe birth defects.

The survey confirmed that the SMART program was not being followed by women or doctors, mainly because the program was not mandatory. The results of the study appeared online on October 14, 2005, in the journal Birth Defects Research (Part A): Clinical and Molecular Teratology.

The survey also revealed that the majority of women were prescribed Accutane off-label for less severe acne than is recommended by the SMART program.

At the December 11, 2002, hearing, the subcommittee discussed the problem of “off-label” prescribing to patients without severe cystic acne and some experts estimated it to be as high as 90% among women.

During the hearing, Roche’s North American president and CEO, George Abercrombie, denied promoting Accutane for patients not suffering from severe acne. When confronted with print advertisements that featured teenage models with little or no visible acne, Mr Abercrombie pointed out that the ads did not specifically mention Accutane and said they were intended to make consumers aware that there were treatments for severe acne.

That statement went over like a lead balloon. “What you just said is not a truthful statement,” Congressman Peter Deutsch (D-FL), told him. “You’re beyond the straight-face test, I’m sorry.”

Due to the failure of the SMART program, and the continuation of babies born with birth defects, in March 2006, the FDA implemented the iPledge program, which basically follows the same rules as the SMART program, but doctors and patients are no longer on the honor system.

IPledge requires a woman to have two pregnancy tests before the initial prescription for Accutane is written, and to have a monthly pregnancy testing before each refill. But now, the prescribing doctor is required to register the test results in the computerized iPledge system, and the woman must fill her prescription within seven days.

In addition, the woman must agree to use two forms of birth control while using the drug and she must also register with the iPledge system to certify that she is using two forms of contraception.

It could be said that Roche has between 300 and 450 good reasons to keep selling Accutane off-label to as many women as possible each month, because according to an August 21, 2006 article by the Associated Press, the daily pill costs between $10 to $15 a pop.

Lawmakers Sever Ties Between CDC and Big Pharma

Evelyn Pringle August 21, 2006

In the wake of overhauling the FDA, lawmakers are also cracking down on conflicts of interest within the Centers for Disease Control.

Last month, Representatives, Dr Dave Weldon (R-FL), and Carolyn Maloney (D-NY), held a press conference to announce the introduction of a bill that would give responsibility for vaccine safety to an independent agency within the Department of Health and Human Services, and remove most vaccine safety research from the CDC.

Specifically, they said on July 26, 2006, the “Vaccine Safety and Public Confidence Assurance Act of 2006,” will create an independent office to address, investigate, and head off potential safety problems like the use of mercury in vaccines, in an objective and non-conflicted office whose sole purpose is vaccine safety and evaluation.

According to Dr Weldon in a prepared statement, Federal agencies charged with overseeing vaccine safety research have failed. They have failed to provide sufficient resources for vaccine safety research. They have failed to fund extramural research and they have failed to free themselves from conflicts of interest that serve to undermine public confidence in the safety of vaccines, he said.

“The American public deserves better,” Dr Weldon stated, “and increasingly parents and the public at large are demanding better.”

“There’s an enormous inherent conflict of interest within the CDC,” he said, “and if we fail to move vaccine safety to a separate independent office, safety issues will remain a low priority and public confidence in vaccines will continue to erode.”

He said that similar conflicts have been remedied in other federal agencies, but in the vaccine program the conflicts persist unchecked. “This bill will provide the independence necessary,” Dr Weldon said, “to ensure that vaccine safety research is robust, unbiased, and broadly accepted by the public at large.”

“Vaccines do wonders for public health, but when the government requires them, it must also ensure that they’re safe,” Ms Maloney said in her statement. “We need adequate, unbiased research on vaccines, and this legislation would deliver that.”

She applauded Dr Weldon for his tremendous commitment and leadership on the issue. “He is truly dedicated,” she said, “to protecting our children and the public at large.”

While announcing the new bill, Dr Weldon and Ms Maloney were joined by several groups advocating vaccine safety reform, including the National Autism Association, A-Champs, and safeMINDS.

According to the National Autism Association: “This landmark legislation will provide critical government agency oversight and implementation of vaccine safety research, which has not kept pace with the rise in the number of vaccines routinely prescribed to consumers including pregnant women and young children.”

Additionally, the Act calls for $80 million in funding to conduct vaccine analysis and safety research.

Currently the CDC oversees vaccine research, safety and promotion, a situation that has been drawing more and more public criticism in recent years. The CDC compiles the list of vaccines that doctors are to give all children in the US, based on the recommendations of an advisory panel, and in many states kids can not attend day care or public schools unless they have received the CDC-endorsed vaccines.

A recommendation by the CDC guarantees a huge market for a vaccine and enables the drug company to use the government as a marketing device for its product. The annual global market for vaccines is expected to be over $10 billion this year.

On July 21, 2003, United Press International published a report based on a four-month investigation that found a pattern of problems linked to vaccines recommended by the CDC, as well as a web of close ties between the agency’s advisory panel and the pharmaceutical industry.

By investigating members of an advisory panel of outside experts that make vaccine recommendations, UPI found that members of the panel received money from vaccine makers through relationships that included: sharing a vaccine patent; owning stock in a vaccine company; payments for research; money to monitor vaccine testing; and funding for academic departments.

In fact, according to UPI, the CDC itself is in the vaccine business. Under a 1980 law, UPI found the CDC had 28 licensing agreements with drug companies and one university for vaccines or vaccine-related products and eight ongoing projects to collaborate on new vaccines.

For instance, the CDC and SmithKline Beecham worked together on the Lyme-disease vaccine. A 1992 CDC activity report, obtained by UPI, says the agency had an agreement “with SmithKline Beecham that currently funds three positions at (the CDC) for the purpose of providing information of use in developing advanced test methods and vaccine candidates.”

In June 2001, the General Accounting Office delivered a report on the issue to Senator Chris Dodd, (D-Conn), that noted that CDC employees “are listed on two Lyme-disease related patents” including “a 1993 joint patent between CDC and SmithKline Beecham Corporation.” The report also said that six of 12 consultants working for the CDC on Lyme vaccines “reported at least one interest related to a vaccine firm.”

According to CDC meeting transcripts where the committee weighed its recommendation, 3 had conflicts of interest with SmithKlineBeecham. The LYMERIX lyme-disease vaccine was approved by the CDC on February 18, 1999, and by October of 2000, more than 1.4 million people had received the vaccine.

But 18 months later, according to UPI, in February 2002, SmithKline Beecham pulled the vaccine off the market claiming that sales of LYMERIX were insufficient to justify the continued investment. However, according to UPI, the company also faced hundreds of lawsuits by people who said they suffered side effects from the vaccines.

The government’s database at the time, listed possible side effects from LYMERIX as 640 emergency room visits, 34 life-threatening reactions, 77 hospitalizations, 198 disabilities and six deaths after people took the shots since the CDC endorsed it, according to UPI.

UPI also found other cases where vaccines endorsed by the panel were pulled off the market after a number of people suffered devastating side effects, and some died.

Congressman Dan Burton, (R-Ind), had already been investigating the advisory panel for several years, and told UPI that the conflicts of interest were a major problem. “This presents a real paradox,” he said, “when the CDC routinely allows scientists with blatant conflicts of interest to serve on influential advisory committees that make recommendations on new vaccines, as well as policy matters.”

“All the while these same scientists,” Representative Burton said, “have financial ties, academic affiliations, and other vested interests in the products and companies for which they are supposed to be providing unbiased oversight.”

An August 2001 report on the investigation by Rep Burton’s House Government Reform Committee, stated that “four out of eight CDC advisory committee members who voted to approve guidelines for the rotavirus vaccine in June 1998 had financial ties to pharmaceutical companies that were developing different versions of the vaccine.”

Critic say the conflicts of interest of Dr Paul Offit while sitting on the advisory panel could not be more blatant. He was part of the team that mandated the use of the RotaVirus vaccine, even though he received a $350,000 grant from Merck to develop the vaccine, shared the patent, and was paid to go around the country teaching doctors that vaccines were safe, according to the Wall Street Journal.

UPI discovered that Merck also had bought and distributed copies of a book written by Dr Offit titled, “What Every Parent Should Know About Vaccines,” to physicians with a Dear Doctor letter that stated:”Merck Vaccine Division is pleased to present you with a copy of the recent publication, ‘What Every Parent Should Know About Vaccines.'”

“The authors designed the book,” Merck’s letter told doctors, “to answer questions parents have about vaccines and to dispel misinformation about vaccines that sometimes appears in the public media.”

The book had a list price of $14.95, and Dr Offit told UPI that he did not know how many copies Merck had purchased.

In 2001, Congressman Burton’s investigation also found conflicts of interest with the then chairman of the advisory panel, Dr John Modlin, a Professor at Dartmouth Medical School, who owned $26,000 worth of Merck stock.

In a phone interview in 2003, Dr Modlin told UPI that he had sold the Merck stock, but that he had recently agreed to chair a committee to oversee Merck vaccine clinical trials.

“Meeting transcripts over the past decade,” UPI says, “showed that at some meetings, half of the members present had potential conflicts with vaccine manufacturers.”

For instance, at a June 2002 meeting, four of the 11 members on the panel acknowledged conflicts with Wyeth, GlaxoSmithKline, Merck, Pfizer, Aventis Pasteur, and Bayer. Two of the four conducted research or vaccine trials and one member was a co-holder of a patent.

The agency is currently facing a major credibility crisis over the issue of whether vaccines containing the mercury-based preservative, thimerosal, are responsible for the epidemic of neurological disorders ranging from ADHD to autism in children all across the country.

The CDC is being accused of research manipulation and cover-ups of vaccine maker culpability by an ever increasing number of activist groups and is also facing tough questions from some of the powerful members of Congress, both Republicans and Democrats alike.

The CDC continues to claim that there is no evidence to support a connection between the epidemic and thimerosal, which they say is no longer used in most pediatric vaccines.

It is however, included in the flu vaccine currently recommended for all pregnant women and children more than 6 months old.

Earlier this year, a group of lawmakers initiated a new investigation of the matter and basically directed the CDC to butt out. On February 22, 2006, they stated in a letter: “If the federal government is going to have a study whose results will be broadly accepted, such a study cannot be led by the CDC,” in a letter to Dr David Schwartz, Director of the National Institute of Environmental Health Sciences.

The letter was signed by Senators, Joe Lieberman (D-Conn) and Debbie Stabenow (D-Mich), and members of the House Representatives including, Dr Dave Weldon, (R-Fla) Chris Smith, (R-NJ), Carolyn Maloney, (D-NY), Dan Burton, (R-Ind), Joseph Crowley, (D-NY), and Maurice Hinchey, (D-NY).

The Institute of Environmental Health Sciences is part of the National Institutes of Health, and was asked to convene a panel to decide how to analyze the CDC database to determine whether autism rates have dropped since thimerosal was removed from most vaccines.

The controversy picked up traction in April, “National Autism Month,” when world renowned heavy metal experts, researchers, and physicians traveled to Washington and rallied on Capital Hill moving the debate beyond just the parents of autistic children.

This spring, a full-page ad appeared in USA Today, the most widely-circulated newspaper in the US, and accused the CDC of “causing an epidemic of autism” by recommending that kids receive a series of vaccinations that contained thimerosal at least as late as 2001.

The ad quoted one of the most recent and famous advocates to join the cause, environmental lawyer, Robert F Kennedy Jr, as saying: “It’s time for the CDC to come clean with the American public.”

The ad was funded by a coalition of advocacy groups led by Generation Rescue, and directed readers to the web site, http://www.PutChildren First.org, to view internal CDC documents, many of which were obtained under the FOIA, that includes transcripts of meetings and e-mails that the groups contend support their allegations of a CDC cover-up.

Congressman Weldon has a theory about why the CDC continues the charade of denying the link between vaccines and autism. “If it is eventually determined that an entire generation of kids was essentially poisoned,” he says, “a class-action suit against the federal government could be on the order of hundreds of billions of dollars, and so there’s very good reason for them to try to cover this up.”

And Dr Weldon’s prediction is proving true. Vaccine injury lawsuits are being filed and won against the vaccine makers and the government. Implemented in 1988, the National Childhood Vaccine Injury Act of 1986, established a mandatory, federally administered no-fault claims process for individuals who allege that they were harmed by the administration of childhood vaccines.

The vaccine compensation fund was created to supposedly ensure an adequate supply of vaccines, and to stabilize vaccine costs. A small fee charged on each vaccines funds the program. According to statistics on the vaccine compensation web site, in fiscal year 2006, a total of $38.2 million has been paid out in cases involving 47 awards.

In what is reported to be one of the largest settlements ever, in July 2006, a quadriplegic boy was awarded $43.1 million. The case alleged that now 7-year-old, Mario Rodriguez, became a quadriplegic after receiving a measles, mumps and rubella vaccine on January. 25, 2000.

Under the guidelines of the vaccine compensation fund program, the lawsuit was filed against the Department of Health and Human Services. Kansas City attorney, Leland Dempsey, who represented the child, told the Kansas City Star: “One unusual aspect of the case is that Mario is expected to have a normal lifespan, and therefore will require more years of care that will cost more money.”

“He will need round-the-clock care, including extensive medical intervention, throughout his life,” Mr Dempsey said.

Many other vaccine related lawsuits have been filed against drug makers. For instance, Eli Lilly, the company that invented thimerosal back in the 1930s, informed its shareholders in its 2005 Annual Report filed with the SEC on April 1, 2006: “We have been named as a defendant in approximately 340 actions in the U.S., involving approximately 1,020 claimants, brought in various state courts and federal district courts on behalf of children with autism or other neurological disorders.”

Lilly also stated, we believe that “the majority of the cases should not be prosecuted in the courts in which they have been brought because the underlying claims are subject to the National Childhood Vaccine Injury Act of 1986.”

Under the Act, claims must first be brought before the US Court of Claims for an award determination under the guidelines established by the Act. However, as Lilly points out in its filing, “Claimants who are unsatisfied with their awards under the Act may reject the award and seek traditional judicial remedies.”

Medtronic’s Medical Device Legal Troubles far from Over

Evelyn Pringle July 31, 2006

Minneapolis based Medtronic, Inc. is one of the nation’s largest medical device makers. In mid-July 2006, the company agreed to pay a $40 million fine to settle charges that its Sofamor Danek division paid kickbacks to doctors to get them to use the company’s spinal products, which accounted for 20% of the company’s $11.3 billion in sales in 2005.

On July 19, 2006 the US Department of Justice issued a press release announcing the settlement. The DOJ alleged that, between 1998 and 2003, Medtronic paid kickbacks in a number of ways, including sham consulting agreements, sham royalty agreements and lavish trips to desirable locations and that these kickbacks violated the Anti-Kickback Statute and the False Claims Act.

“Kickbacks to physicians are incompatible with a properly functioning health care system,” said Peter Keisler, Assistant Attorney General for the DOJ’s Civil Division. “They corrupt physicians’ medical judgment and they cause overutilization and misallocation of vital health care resources.”

“Today’s settlement,” he added, “reflects the progress we are making in the ongoing fight against abusive and illegal practices in the healthcare industry.”

The DOJ’s investigation was triggered by whistleblower qui tam lawsuits filed under the False Claims Act. The FCA allows private parties to file lawsuits on behalf of the US government and collect a share of any money recovered. The FCA prohibits any corporation or citizen from defrauding the government and the allegations against Medtronic in this instance involve the Medicare program.

“The settlement,” said David Kustoff, the US Attorney for the Western District of Tennessee in the press release, “demonstrates that schemes involving submissions of false or fraudulent claims by health care companies and health care providers to federal health care programs will be vigorously and energetically pursued.”

“This agreement,” he noted, “should serve as a deterrent to those entities that attempt to defraud or deceive the taxpayers.”

In addition to the fine, Medtronic entered into a 5-year corporate integrity agreement with the Office of the Inspector General of the US Department of Health and Human Services. The agreement requires the company to file regular reports with the Inspector General and track all non-sales related customer transactions.

The company must also set up an outside review organization, improve training and employee screening practices, and make a compliance officer a member of senior management, who reports directly to the chief executive and has access to the company’s board of directors

The two whistleblower lawsuits filed by former employees claim Medtronic paid millions of dollars in kickbacks. For instance, Dr Thomas Zdeblick, a Wisconsin surgeon who is listed as a defendant in one of the lawsuits, signed a 10-year consulting contract with the company in 1998, that only required him to consult with Medtronic for eight days a year for $400,000.

A Virginia physician received close to $700,000 in consulting fees for the first 9 months of 2005, and received $1.39 million between 2001 and May 2005, according to the lawsuit.

Internal Medtronic documents filed as part of the lawsuit in the US District Court in Memphis, reveal the details of the rigorous campaigns that Medtronic set up to influence doctors. The documents show the company made payments of at least $50 million to doctors over a four years period through June 2005.

In the lawsuit unsealed in January 2006, the plaintiff, Jacqueline Poteet, a former senior manager of travel services for Medtronic until 2003, says she handled the travel arrangements for doctors to attend medical conferences and is familiar with the company’s efforts to win the doctors’ favor.

She alleges that the company gave spine surgeons “excessive remuneration, unlawful perquisites and bribes in other forms for purchasing goods and medical devices.”

Spinal implants are used in a procedure known as spinal fusion, to make a patient’s spine more stable. The cost of a devices used in this type of surgery is about $13,000, according to Orthopedic Network News, an industry newsletter.

In a subsequent amended complaint, Ms Poteet, accuses the company of continuing the improper payments to doctors in 2004 and 2005, leading them to perform unnecessary spinal surgeries.

With billions of dollars up for grabs, in addition to consultant fees, Medtronic used other creative methods to induce physicians to use its products. According to the lawsuit, Medtronic hosted medical conferences where the “principal objective” was to “induce the physician, through any financial means necessary” to use its devices.

Company spreadsheets show that after a conference, Medtronic went to great lengths to track the use of its devices by each doctor who attended. A spreadsheet for a June 2003 conference in California, lists over 200 doctors and includes an estimate of the dollar amount of the devices each doctor uses in surgery. One surgeon is described as “a 100 percent compliant M.S.D. customer” (Medtronic Sofamor Danek), and other doctors are marked as needing “special attention.”

According to Ms Poteet, Medtronic zeroed in on surgeons while they were still in training, and the company paid for doctors to attend any of 200 professional meetings a year. If the doctors wanted to play golf or go snorkeling, she alleges, Medtronic paid for the outings. When doctors visited Memphis, she says, company employees would take them to the “Platinum Plus” strip club, and then write off the expense as an evening at the ballet.

In 2003, a company document reveals that Medtronic attorney, Todd Sheldon, questioned whether the company should be paying for all the excursions. “When we are sending scores of doctors to a nice resort like this under the guise of training and education on our products,” Mr Sheldon wrote in an email, “I think we need to be more careful and stick to the limits of our rules as best we can.”

Medtronic claims the company has scaled back payments to doctors, but not so, says Ms Poteet. Her amended complaint alleges that any changes made by Medtronic were merely temporary. Its “bribery program,” she alleges, “has not only failed to cease, but continues unabated with increased payments made to many physicians.”

She points out that while payments to some doctors were lowered in 2004, when the company first came under investigation, the payments went back up last year. For instance, Dr Hallett Mathews, of Virginia, was paid $300,000 in consulting fees in 2003, but only $75,000 in 2004. But then in 2005, he was paid nearly $700,000 in consulting fees in the first 9 months.

Had Medtronic not entered into a settlement agreement with the DOJ, the company could have been hit with a triple damages award if it lost in court, under a key provision of the FCA. As it is, the $40 million fine is the second financial penalty for Medtronic’s spinal division in a year. In 2005 the company paid $1.35 billion to settle a patent infringement lawsuit and cover the costs of additional patents from Los Angeles surgeon and inventor, Dr Gary Michelson.

Over the past couple years, the financial relationships between device makers and doctors have caught the attention of several law enforcement agencies. In 2005, US attorneys in Boston and Newark issued subpoenas to Medtronic, along with just about every other major medical device maker, as part of a far reaching investigation into the financial entanglements between physicians and the industry as a whole.

Therefore, legal experts say Medtronic is probably not breathing much easier these days. Three of the subpoenas issued last fall went to the top cardiac-rhythm-management companies, Medtronic, Guidant and St Jude Medical, and seek information on their marketing practices related to pacemakers and defibrillators.

And Medtronic already had plenty of legal problems with its defibrillator division. In February 2005, the company told 87,000 patients that their defibrillators might fail.

However, company documents filed in the California lawsuit, Randall v Medtronic, No C-05-3707-JW, in the US District Court for the North District of California, show the company knew about the flaw back in 2003, and continued to sell the faulty devices for two more years.

“Medtronic has been taking products they know are not quite right and putting them into people rather than take the loss,” according to Hunter Shkolnik, a New York attorney, who said in a February 13, 2006, interview with Bloomberg News, that he represents more than 200 people whose Medtronic devices were recalled.

“If you know there’s a problem with a component,” he said, “you don’t put it out and sell it to people.”

Since the recall, 19,000 people have had replacement surgery, Medtronic spokesman, Rob Clark, told Bloomberg News.

Critics say Medtronic refuses to acknowledge that undergoing replacement surgery is risky and constitutes an injury in itself. According to Bloomberg, based on Medtronic’s estimate of a 2 to 5% post-implantation infection rate, 380 to 950 patients may have developed infections after replacement of their devices.

Spokesman Clark told Bloomberg that Medtronic does not keep track of deaths, disabilities or extra medical costs resulting from such complications.

When announcing the recall last year, Medtronic said it would provide a new defibrillator to patients and up to $2,500 for out of pocket expenses. But the company expects taxpayers, through programs like Medicare, and insurance companies, to pick up the tab for the hospital and doctor bills incurred during the replacement surgery.

However, the company is now facing scores of lawsuits claiming that patients should not be expected to bear any of the costs for having the devices replaced. About 200 lawsuits from states all over the country are seeking class-action status and have been consolidated in US District Court in Minneapolis before Judge James Rosenbaum.

Last month, Medtronic asked the Judge to dismiss the lawsuits, arguing that FDA regulations for medical devices preempt lawsuits in state courts and that the FDA has special authority over lifesaving or life-sustaining medical devices, such as defibrillators. “Any warning has to be regulated by the FDA,” Medtronic attorney, Michael Brown, said.

But attorneys for the plaintiffs said Medtronic “glossed over” the problem in an October 2003, filing with the FDA that sought approval of a new defibrillator model, according to a July 11, 2006, article by the Associated Press.

Judge Rosenbaum is expected to issue a decision on Medtronic’s motion in early fall.

Six months after the first recall in 2005, the company was in hot water with the FDA again over another group of devices. In a June 9, 2005 letter, the FDA said that Medtronic failed to correct manufacturing problems and investigate its LifePak 12 external defibrillators and cited damaged cable connectors and failures to follow through with preventive action after inspections of the company’s Redmond, Washington plant.

The LifePak 12 external defibrillators, used in hospitals to shock the heart back to a normal rhythm, are similar to the LifePak 500 devices the company recalled. Medtronic’s cardiac rhythm management business, which also includes pacemakers and implantable defibrillators, accounted for 46% of its $2.78 billion in sales in its latest quarter, according to Bloomberg News on June 22, 2005.

At the time, about 60,000 LifePak 12 external defibrillators were in use worldwide, Mr Clark said.

In the warning letter, the FDA said Medtronic did not investigate all complaints about defibrillator malfunctions, including one involving a patient’s death. Problems were linked to broken or bent pins in the cable connectors, possibly because the company did not have adequate inspection procedures, the agency said. Failure to correct the problems may result in legal and civil penalties, the FDA warned.

Finally, in another turn of events that could have a negative impact on the financial future of the company, Medtronic is awaiting the final word on a Medicare proposal that would decrease reimbursement for procedures that are considered excessively profitable such as implanting heart devices.

Under the pending proposal, the Medicare reimbursement for implants would be cut from $31,833 to $23,755, or a loss of $8,078 for each procedure.