Our law firm has tried eight trials in a row to successful plaintiffs’ verdicts; involving what has become known as the “Engle Progeny Cases”. These cases arise from the “Engle” case tried two decades ago in which juries heard 12 months of evidence and made a series of findings about cigarettes. Subsequently, the Florida Supreme Court found the following facts about the conduct of tobacco companies including:

• Cigarettes are addictive.
• Tobacco companies concealed important information about the dangerous health effects and the addictive nature of cigarettes from the public.
• Smoking cigarettes cause over 20 different diseases.
• Cigarettes are a defective product placed in the market by tobacco companies.
• Cigarettes are unreasonably dangerous as manufactured by tobacco companies.
• Tobacco companies conspired to conceal from the public important information about cigarettes and the dangers of smoking.
• Tobacco companies were negligent.

Those of us in this law firm who have worked on cases against the tobacco companies have read the documents used in the Engle case and other cases, including the Minnesota Attorney General’s case. Once you read and review those documents it could not be clearer that all of the findings by the Florida Supreme Court set forth above are absolutely, crystal clear. In fact, because so much evidence and so many documents exist, most of it is never exhibited at the trials of cases against tobacco companies by tobacco company victims – most jurors never see but a small fraction of all of the evidence available .

We have seen the evidence of an industry that has made a science out of hiding, lying and manipulating. We have seen the documents summarizing plans by the tobacco companies to manipulate the nicotine in cigarettes; to create marketing plans that target teenagers; and to create “scientific” data in order to support the message that smoking cigarettes is actually good for you. Tobacco’s marketing plans for doctors to tell the public that smoking is good for you; athletes talking about smoking cigarettes improving their “wind”; and movie stars glamorizing the entire smoking genre – all are diabolically brilliant.

So, quite frankly, members of our firm were not at all surprised that we received two verdicts in favor of our clients and against the tobacco companies; in two different trials; tried in two different parts of Florida. The fact is that when anyone involved in the trial of tobacco cases hears about a verdict in favor of the tobacco companies, we are, well, shocked.

It is inspiring that two juries; in two different geographic locations; with two different sets of lawyers, can reach the same conclusion: the tobacco industry addicted people to a drug they knew was one of the single most addictive drugs in existence and then further manipulated that drug to increase its desperate hold on smokers. Then this industry literally invented the art of propaganda marketing and threw billions of dollars to make it successful.

We are pleased that our clients received their opportunity for justice in receiving verdicts of $3.5 million in one case and $2.7 million in another case. We would also like to recognize the talented attorneys who tried these cases: James Gustafson, Matthew Schultz (Levin, Papantomio law firm), Brian Denney, and Hardee Bass.

These were truly victories for “the good guys”.

You wouldn’t let your toddler play in a busy street. That’s just good common sense that you already know. However, if you’re in a more precarious position—perhaps you’re pregnant and depressed—you need expert guidance you can trust to keep you healthy and your baby out of danger. You should be able to turn to the medical profession to steer you in a safe direction, right?

In your highly vulnerable state, the pharmaceutical and medical industries have assured you that there’s almost no risk in taking medications like antidepressants during pregnancy. But are they using common sense?

The British Medical Journal released a study last week that examined 1.6 million births from 1996 to 2007 and found that women who take selective serotonin reuptake inhibitors (SSRI) antidepressants late in their pregnancy are twice as likely to give birth to a baby with pulmonary hypertension.

This condition occurs when a newborn has high blood pressure in its lung and the lungs do not adequately adapt to breathing on their own after birth. It’s a dangerous disorder that can lead to organ failure, brain damage or even death. About one in every 1,000 babies is born with the condition.

Yet some experts are discounting the severity of the study’s findings. “You’re doubling the risk of extremely low risk to again, an extremely low risk,” Dr. Marjorie Greenfield, division director of obstetrics and gynecology at University Hospitals Case Medical Center in Cleveland, told ABC News.*

Yes, and maybe there’s an extremely low risk that a driver won’t swerve his car in time to avoid hitting your kid.

But there’s a lot at stake in maintaining the “good name” of antidepressants. SSRIs hit the market in the 1980s and ’90s and gave hope to many people battling depression, eating disorders, post-traumatic stress disorder and obsessive-compulsive disorder. Medications like Prozac (fluoxetine), Zoloft (sertraline) and Lexapro (escitalopram) offered a safer, more effective answer to their side effect-plagued predecessors.

Today, antidepressants are the third most widely prescribed drugs in America, with 1 in 10 Americans taking some form of the drug, according to the Centers for Disease Control and Prevention. This translates into $20 billion in annual profits for pharmaceutical giants like Eli Lilly, Pfizer and Forest Pharmaceutical.

SSRIs work by targeting serotonin, a neurotransmitter that sends messages in the brain. The theory is that a serotonin imbalance will lead to mood variations and depression—or, conversely—that depression will cause a serotonin imbalance. It’s not known which comes first or even exactly how SSRIs work in the brain, other than that they seem to wash away the blues.

People who take SSRIs are subject to side effects that range from restlessness to committing suicide. And while depression during pregnancy can also be dangerous, is the risk worth the benefit? This isn’t the first time that question has been asked. To wit:

• In 2009, a Dutch study of 39,000 children found that those who had mothers who took antidepressants were more likely to have respiratory and digestive problems.
• A Denmark study released in 2010 followed 82,000 babies and discovered that those whose mothers took antidepressants had slight delays in reaching developmental milestones like sitting up and walking.
• A small Kaiser Permanente study in 2011 suggested a link between a pregnant woman’s SSRI intake and her baby’s chance of developing autism.

In addition, it is well known that newborns of mothers who take antidepressants like SSRIs are often jittery and cry excessively during their first month of life, likely due to the fact that stopping SSRIs abruptly causes irritability and is highly discouraged due to these withdrawal symptoms. But when you leave the womb laced with SSRIs, you don’t have much of a choice.

Yet antidepressants are still widely prescribed to pregnant women who are battling mood swings, highs and lows and emotion turmoil during their babies’ development. Are the manufacturers of these medications and physicians who dole them out trying to lead you through a healthy pregnancy and offering a variety of feasible treatment options…or are they sending your unborn baby out into oncoming traffic? Where’s the common sense there?

Let’s say you want to form a committee to evaluate the safety of a drug; say for example the drugs Yaz, Ocella and Yasmin.

You begin by looking for people who are “experts” about the drug, the ingredients in the drug and the use of the drug.

You find 26 or so people who fit your criteria.

Do you want to eliminate those people who may, might, could, have a conflict of interest; a “dog in the fight”; a prejudice one way or the other about the drug or its ingredients or its use?

If you are forming this committee as a public safety body, wouldn’t you also want to eliminate those individuals who even have “an appearance of conflict” in being independent about their evaluation of the drug?

I think any objective person would answer “yes” to both these questions. The Food & Drug Administration – well, they apparently do not subscribe to the same tenets for evaluating potential conflicts of interest as most of the rest of us.

On December 8, 2010, the FDA convened a committee to evaluate the safety and continued sale of Bayer’s drug Yaz. Yaz, Yasmin and Ocella and drospirenone as an ingredient. These drugs have been linked to an increased level of stroke, heart attack, pulmonary embolus and a number of other life threatening conditions in women who used them and otherwise had no risk factors for these conditions. It has been fairly established that these birth control drugs caused the life threatening and, in some cases, life ending conditions for thousands of women.

It also seems pretty clear that Bayer was less than forthcoming about the dangers associated with Yaz, Ocella, and Yasmin. In fact, there have been allegations that Bayer actually knew and consciously withheld important data from the Food & Drug Administration.

So, given all this “gray matter” surrounding the drug, you would want your conduct, as a regulator, to be beyond reproach, right? Testimony from a former FDA regulator, David Kessler, about some of the committee members raises concerns; perhaps not actual conflicts, but certainly potential conflicts suggesting that Bayer may have felt “owed” something by these committee members:

• One of the committee members was considered a “Bayer trained speaker” and was involved in promotional programs for Bayer. This same physician was in the Bayer speaker program and helped Bayer by reviewing research materials related to Yaz. This member also participated in video promotions on behalf of Bayer.
• A second committee member was listed as a “Bayer Contraception Expert” and apparently conducted research for a company that Bayer eventually purchased. The research the physician was involved in related to the use of drospirenone, which, of course, is the key ingredient in Yaz, Yasmin and Ocella.
• A third is listed by Bayer as a “key opinion leader” and an “external expert”.
• The fourth committee member apparently performed at least four research projects for Bayer; including one involving, yes, you guessed it, drospirenone. All four research projects seem to relate directly to contraceptive drugs.

In a paper filed with the court, Bayer now seeks to exclude the testimony of Dr. David Kessler; who believes these potential conflicts are important. In their court paper, Bayer does not argue that what Dr. Kessler states is untrue; rather Bayer argues that, for legal reasons, he should not be permitted to testify about his findings.

Does this all mean that the members, and possibly others, in the committee voted in favor of Bayer being allowed to keep its billion dollar money maker drug on the market? Not necessarily. That is not the point.

The point is that we will never know for certain.

No one should sit in judgment of whether a drug is or is not too dangerous to remain on the market if they have even the “appearance of” a conflict of interest. Why risk it? Why risk the potential of exposing the public to unnecessary risk if, in fact, a drug is too dangerous, but remains on the market because someone did have a “dog in the fight”?

The point is that these circumstances fairly raise the question of exactly who is really running the FDA and who does the Food & Drug Administration really work for in safety vs. marketing situations.

Big Tobacco has recently agreed to pay over $6 million to settle claims with the US Department of Justice.

A summary of the conduct causing the $6 million payment?

US district Court Judge Gladys Kessler, after hearing mountains of evidence, says this about the tobacco corporations:

• They lied.
• They misrepresented the truth.
• They deceived.
• They concealed.
• They destroyed documents.
• They distorted the truth.
• They abused the legal system.

They conspired to keep away from the public scrutiny documents that demonstrate “smoking’s negative health effects, nicotine addiction, and altered cigarette design to increase addiction, light- and low-tar cigarettes and marketing to young consumers”.

Judge Kessler went on to say:

“In short, defendants have marketed and sold their lethal product with zeal, with deception, with a single-minded focus on their financial success, and without regard for the human tragedy or social costs that success exacted”.

But, Big Tobacco did not act alone. Judge Kessler also had comments about Tobacco’s lawyers: they “played an absolutely central role in the creation and perpetuation of the enterprise and the implementation of its fraudulent schemes”.

These findings and Big Tobacco’s willingness to pay millions in order to avoid an airing of the evidence in a court of law come as no surprise to attorneys who have had to litigate against them. Simply reviewing the tobacco documents that have not been destroyed or hidden by Big Tobacco leads to only one conclusion. The tobacco industry has spent a hundred years perfecting a talent for hiding the truth and spinning facts to a point that fact becomes fiction.

Big Tobacco wrote the playbook for all other corporations who have held “shredding parties” and data dumping get-togethers in order to hide their wrongdoing.

Corporate America needs protection from trial lawyers!?

So goes the tort reform mantra. Trial lawyers are victimizing corporations; which is causing job loss; which is ruining the economy; which is leading to higher prices; which is causing Wall Street uncertainty; which is leading to all around chaos.

I have worked for Corporate America and I have worked for lawyers. All the lawyer jokes aside, I am happy to no longer be working in the moral ambiguity of Corporate America.

Let’s take today’s Corporate citizenship example. Pfizer, Inc.

Recently, Pfizer agreed to pay fines of a record amount, $2.3 billion, for hiding off-label drug marketing practices. That would be the practice of selling drugs for uses that the FDA has not approved them for or, in some cases, uses that the FDA has specifically prohibited. Now, Pfizer investors are suing Pfizer saying that the Corporate Pharma “promised” it would stop its off-label marketing practices, but $2.3 billion later proves otherwise.

Also, just unsealed yesterday, is a complaint filed against Pfizer for the marketing of its drug, “Vfend” (voriconazole); an antifungal medication approved for the treatment of invasive aspergillosis and candidemia. Pfizer requested FDA approval to market the drug as “empiric therapy” as well. Empiric therapy is the medical practice of initiating treatment before an actual diagnosis can be made based upon laboratory or other objective studies. Antibiotics and some antifungals are often prescribed, quite correctly, by physicians based only upon their judgment of a patient’s symptoms. Pfizer wanted the ability to market Vfend on this broad basis so that physicians would prescribe it more often and, thus, increase Pfizer’s profits proportionally.

The FDA refused to allow Pfizer to market Vfend as an empiric therapy. So, what did Pfizer do? You guessed it, they marketed Vfend for broad use anyway. Why would a corporation specifically violate FDA regulation?

Vfend was approved for the limited use of treating diagnosed fungal infections in 2002. Certainly, the fact that Pfizer made $825 million in 2010; $798 million in 2009; and $743 million in 2008 off the drug may have played into their decision. Also, Vfend was designed to replace an antifungal, Diflucan, for which Pfizer was losing its US patent. Diflucan had been generating annual sales for Pfizer averaging $1.1 billion per year – an amount they stood to lose if they could not replace Diflucan with a substitute.

The current lawsuit brought by the US government was the result of company “whistleblowers”; former employees of Pfizer who have provided information to the US government suggesting that Pfizer’s off-label marketing resulted in much higher sales and this resulted in a fraud upon Medicare and Medicaid.

Sour grapes from some disgruntled employees? Let’s take a look at those employees; both of whom reportedly resigned from Pfizer:

Catherine Brown was Senior Marketing Manager at Pfizer and had been employed by them from 1996 to 2005. She holds multiple degrees in science and business and she was, in fact, “Representative of the Year” in 1998. She resigned from Pfizer in 2005

Bernard Vezeau was a Senior Product Manager on the “Vfend Marketing Team”. Mr. Vezeau went to West Point, was a Captain in the US Army and held a Master’s degree in Business Administration. He worked for Pfizer between 1989 and 1992; and was rehired by them in 2003.

The complaint brought by the US government gives insight into what allegedly occurred. Apparently, Pfizer was using a study, “the 608 Study” to substantiate its claims that Vfend was effective in treating broad categories of fungal infections. Notably, Pfizer claimed that Vfend was effective in treating a very aggressive and potentially lethal fungal pathogen, C. glabrata. The problem explained in the complaint in detail is that the 608 study results were, first, of a small patient population and, second, the results were substantially manipulated by Pfizer in an effort to cause the study to demonstrate an effectiveness in treating broad categories of fungal infection when it, in fact, was not effective.

While Pfizer marketed Vfend as having an “extended spectrum” and recommending physicians use Vfend “at the earliest clinical suspicion of a fungal infection”, respected medical journals condemned these assertions. The New England Journal reviewers stated that the 608 study “significantly obfuscate the presentation of results” and found the study “a bit deceptive”. The Lancet published comments by a noted and respected expert in fungal infections as finding the results of the 608 study to be “most perplexing” and seeming “seriously flawed”. In English, they did not believe Pfizer’s study and, if the allegations prove to be true, these experts had good reason.

What did Brown and Vezeau do wrong? Well, from Pfizer’s perspective, they insisted on clarification of the study results and asked for substantiation for claims that Vfend was effective in treating broad categories of fungal infections, most notable a life threatening fungal like, C. glabrata. Pfizer’s medical director, Dr. Dr. Schlamm, allegedly complained that Mr. Vezeau, was asking too many questions about the 608 study.

Now, Pfizer stands accused, yet again, of marketing drugs for uses NOT approved by the FDA. In addition, they are accused of manipulating scientific studies and opinion – for what? To maximize profits.

So, ask yourself: who needs protection from whom?

Increase your possibility for blood clots – take Yaz birth control.

That would be bare truth in advertising were Bayer AG willing to be honest about its block buster contraceptive medication that generated over $1.5 billion in sales last year.

Another truth in advertising for the Yaz drug maker? We were just kidding when we claimed that Yaz was good for clearing up acne and treating all forms of PMS symptoms. We said it, but we did not mean it and, oh yeah, Yaz was never approved for those uses.

In an email discovered during the litigation that has been filed against Bayer, a company official encouraged sales representatives to propose that doctors prescribe Yaz for unapproved, off-label use:

“…what percentage of your patient population suffers from” symptoms common to PMS, versus the more severe form of the disorder, and to seek information on “what they think the impact of Yaz will be.”

Yasmin and Yaz were never approved for treatment of common PMS symptoms.

In another email, a sales representative suggests that a noted gynecologist: “…definitely will mention the off-label benefits of our products.”

We have been writing since early 2009 about Bayer’s less than responsible commercials that used attractive, successful appearing women to promote its drugs Yaz, Yasmin and Ocella while using glitzy advertising to obfuscate the lack of FDA approval for some of its uses and to hide its sometimes lethal side effects.

An upcoming meeting at the FDA, on December 8, 2011, is designed to discuss the fate of oral contraceptives and the studies that have been conducted about them. At least one of the leading studies, conducted by Juergen Dinger then director of the Center for Epidemiology and Health Research, has come under scrutiny. Dr. Dinger is a former employee of the company initially marketing the Yasmin line of oral contraceptives and there have been emails discovered that cast some questionable light on the independence of the study. For example an executive at the company sent a 2005 email talking about the risk of “VTE” and “ATE” (referring to clots in users):

“One major reason for providing only tables and a synopsis is that we do not want to imply that we have a VTE problem but emphasize the fact that the study results indicate that Yasmin’s VTE/ATE is comparable to other” contraceptives.

Like buying “ghost writers”, some companies have sponsored “studies” of their products with the sole goal of supporting the safety of the product, rather than discovering independent, objective findings about their products.

Sadly, $1.5 billion buys a great deal of favorable opinions and provides more than enough motivation for companies to discover supportive findings in any study they conduct.

As I have written many times before, I believe in the jury system, but it requires a well-informed jury, given all the facts and evidence, to arrive at a just decision. Based upon my own research and the below discussion, I must conclude that, more likely than not, the jurors in the case of Hunter v Phillip Morris resulted in a less than full disclosure of the evidence relating to the outrageous conduct of the tobacco industry.

I have read many, many of the documents that comprise those involving Big Tobacco’s evolution in the development and production of cigarettes; evolution and production because what most people think of as tobacco was abandoned by cigarette manufacturers decades ago. What they sold and continue to sell to Americans and the rest of the world is a chemically engineered plant that they have called “the best drug delivery system” ever created.

A federal judge, Judge Gladys Kessler, has also read the documents, heard the testimony and saw fit to condemn Big Tobacco for sins against the American public:

• These cases are about an industry that profits from selling a highly addictive product that causes a staggering number of deaths each year and Big Tobacco has known about the dangers for more than 50 years.
• “Defendants have marketed and sold their lethal products with zeal, with deception, with a single-minded focus on their financial success, and without regard for the human tragedy or social costs that success exacted.”
• “Over the course of more than 50 years, Defendants lied, misrepresented and deceived the American public, including smokers and the young people they avidly sought as ‘replacement’ smokers about the devastating health effects of smoking and environmental tobacco smoke.”
• “The evidence in this case clearly establishes that Defendants have not ceased engaging in unlawful activity…. For example, most Defendants continue to fraudulently deny the adverse health effects of secondhand smoke which they recognized internally; all Defendants continue to market “low tar” cigarettes to consumers seeking to reduce their health risks or quit; all Defendants continue to fraudulently deny that they manipulate the nicotine delivery of their cigarettes in order to create and sustain addiction; some Defendants continue to deny that they market to youth in publications with significant youth readership and with imagery that targets youth; and some Defendants continue to  suppress and conceal information which might undermine their public or litigation position…. Their continuing conduct misleads consumers in order to maximize Defendants’ revenues by recruiting new smokers (the majority of whom are under the age of 18), preventing current smokers from quitting, and thereby sustaining the industry.”
• “Despite Their Internal Knowledge, Defendants Continued, From 1964 Onward, to Falsely Deny and Distort the Serious Health Effects of Smoking”
• “As of 2005, Defendants Still Do Not Admit the Serious Health Effects of Smoking Which They Recognized Internally Decades Ago”

Even a powerful industry like the tobacco companies does not hide, deceive or scheme on their own, though. Judge Kessler also has interesting things to say about lawyers that have counseled and defended the tobacco companies for all these decades:

• “At every stage, (Big Tobacco’s) lawyers played an absolutely central role in the creation and perpetuation of the Enterprise and the implementation of its fraudulent schemes. They devised and coordinated both national and international strategy; they directed scientists as to what research they should and should not undertake; they vetted scientific research papers and reports as well as public relations materials to ensure that the interests of the Enterprise would be protected; they identified “friendly” scientific witnesses, subsidized them with grants from the Center for Tobacco Research and the Center for Indoor Air Research, paid them enormous fees, and often hid the relationship between those witnesses and the industry; and they devised and carried out document destruction policies and took shelter behind baseless assertions of the attorney client privilege.”
• Through their recruiting and training of consultants around the world, Defendants created a cadre of seemingly independent consultants to support the industry’s position on secondhand smoke and to create the impression that a legitimate controversy existed among independent scientists. The global effort to create and manage this program required intense coordination among the companies and their counsel [outside lawyers].

When an objective eye is turned upon all the evidence relating to the conduct of the tobacco industry the conclusions are inescapable. So, how can jurors reach differing verdicts? The lawyers representing Big Tobacco are some of the best in the nation, possibly the world. They have had decades to refine arguments that may convince even the most experienced jurist  to exclude certain relevant evidence.

For example, in a tobacco case brought since the issuance of the Surgeon General’s report on smoking in the 1960’s and after warning labels were put on cigarettes, it might be argued that any evidence of conspiracy or fraud on the part of the tobacco companies that occurred prior to the 1960’s should be kept from the jury. Tobacco lawyers regularly challenge the experts employed by plaintiffs by arguing that those experts are simply reinterpreting prior studies from the past and have done no “independent” testing of their own. The fact is the tobacco industry spent millions of dollars “creating” research results and conducting studies that would bring forth the evidence they wanted revealed; so, actually conducting a study has questionable value.

Once all evidence of Big Tobacco’s conspiracies, fraudulent tactics and deceptive practices hits the “light of day” it Tobacco’s arguments go up in smoke.

It has now been more than a year since the DePuy ASR implant was recalled due to an alarmingly high rate of failure of the device, which was first documented in Australia and Europe years ago, at a time when the hip implants enjoyed continued strong sales in the United States.

For tens of thousands of patients, the past 15 months or so have been ones filled with extreme anxiety, pain, and frustration because of the following:

• Receiving countless empty promises, significant delays, and the proverbial “run around” from the Broadspire “claims program,” which has been far more kind to surgeons and healthcare providers with unpaid bills than to injured patients.
• Experiencing significant fear and apprehension over blood tests showing elevated levels of cobalt and chromium in their bloodstream, without any clear answers as to what harm this might cause them over time and what can be done about it.
• Enduring yet another painful hip implant revision surgery.  In some cases, within mere months of their original surgery (at which time, they were promised by DePuy that they would not have to undergo this ordeal for 15 years or more due to the alleged proven performance and superiority of the DePuy ASR and other metal-on-metal hip implant products over traditional ceramic and plastic liners).

Thousands of patients have suffered significant complications and have had less than favorable outcomes due to the trauma of extra procedures, complications stemming from metallosis and inflammatory reactions to the metal-on-metal surfaces, pseudotumor formation, infections, and other serious side effects.

Thankfully, scientists are working to answer questions that DePuy should have answered long before their first DePuy metal-on-metal device was implanted in patients.  Several studies have been recently published that help to expand the understanding of the systemic reaction that is triggered by metal-on-metal implants in patients as well as why these devices are failing at alarmingly high rates.  The recent most findings by scientists are:

• Cobalt and Chromium Ions Reduce Human Osteoblast-Like Cell Activity In Vitro, Reduce the OPG to RANKL Ratio, and Induce Oxidative Stress, published in the Journal of Orthopaedic Research, on October 24, 2011 – This study focused on how elevated levels of cobalt and chromium in the blood reduce the number of osteoblast-like cells and essentially impair the body’s ability to normally regenerate and maintain healthy bone.  Ultimately, the authors concluded that patients with elevated levels of chromium and cobalt in the blood are at risk for impaired bone health and that consideration should be given to removal of their metal-on-metal hip implants, even when x-rays and other evidence indicate that the DePuy ASR or other metal-on-metal implants are properly positioned without solid evidence of loosening.

• Corrosion Fatigue of Biomedical Metallic Alloys:  Mechanisms and Mitigation, published in the Acta Biomaterialia, in 2011 – This highly complex medical article from Brazil includes a review of the professional literature that has been published around the world on the scientific explanation for the widespread premature mechanical failure of metal-on-metal hip devices due to corrosion.  The study focuses on a number of different metals and alloys including titanium, surgical-grade stainless steel, cobalt, chromium, and magnesium.  The study also focuses on wear patterns, development of fatigue cracks, pitting corrosion, and formation of crevices at the taper junction, which allow infiltration and pooling of bodily fluids that induce corrosion and cause the release of metallic ions.  The processes of corrosion and metal fatigue combine to lead to premature failure of the devices, which necessitated the recall of the DePuy ASR implants, but, so far, has not resulted in the recall of a number of other metal-on-metal devices manufactured by DePuy (including some models in the popular Pinnacle family) as well as similar MOM products manufactured by Zimmer, Stryker, Biomet, Smith & Nephew, and other medical device companies.

• Pseudotumor from a Metal-on-Metal Hip, published in The Journal of Rheumatology, in 2011 – This publication from physicians in Tokyo includes a graphic, intra-operative photograph of a revision surgery where the synovial tissue has been stained due to the metallosis process.  This same staining as well as the presence of abnormal appearing inflammatory fluid and even metal shavings have been noted in other patients, including some of my clients, who have undergone revision surgeries following the DePuy ASR recall.  In the Japanese patient featured in this medical report, the surgeons noted the presence of pseudotumors in the patient’s pelvis, thigh, and gluteal region, which were triggered by a breakdown in the chemical properties of the metallic surfaces of the patient’s hip implant. This patient’s pseudotumors and obvious inflammatory reaction occurred about three years after being implanted with an Encore Medical metal-on-metal hip implant, a product that is now sold by DJO Surgical of Austin, Texas.

While the steady stream of new scientific reports are helpful to patients pursuing lawsuits against DePuy and other manufacturers, it is little comfort to those duped into implanting themselves with a toxic, defective product and are now faced with scary prospects with regard to their medical and surgical future.  While the Food & Drug Administration (“FDA”) has noted that it has been looking into safety issues for the past 15 months, the FDA’s slow pace in issuing stronger safety alerts and/or recalling defective metal-on-metal implants has resulted in tens of thousands of patients not being properly monitored for toxicity due to a lack of awareness by surgeons, patients, and the public.  I hope that the flood of new information will be disturbing enough for the FDA to act more definitively.

There are growing safety concerns over the anti-arrhythmia drug Multaq, (dronedarone), which is manufactured and marketed by Sanofi-Aventis and has generated a great deal of controversy and concern in just a few short years.

Multaq was first approved by the Food & Drug Administration (“FDA”) in 2009 for use as an anti-arrhythmic drug in heart patients with paroxysmal or persistent atrial fibrillation.  Atrial fibrillation is essentially an irregular heartbeat that may be a sign of an asymptomatic problem or may be a sign of a significant and life threatening problem. People with atrial fibrillation are exposed to things such as fainting, congestive heart failure, and stroke. Paroxymal refers to patients with symptoms that resolve in less than (7) days and persistent to patients with symptoms resolving in over (7) days.

The drug, Multaq, was prescribed in particular for patients with severe heart disease, including those who were elderly, had other serious medical conditions such as hypertension or diabetes, a history of a previous stroke or cerebrovascular accident, or had evidence of serious heart disease or heart failure based up on their EKG and echocardiogram findings. The drug carries a “black box warning” (the strongest level of warning on a prescription drug) informing physicians that Multaq should not be prescribed for patients with severe congestive heart failure because of  concerns that use of the drug might worsen patients’ heart failure symptoms or increase their chances of dying.

Here is just a glimpse into the questionable history of Multaq:

• July 1, 2009 – Multaq, (dronedarone hydrochloride), was approved by the FDA for sale in the United States.  The drug was subject to a Risk Evaluation and Mitigation Strategy (REMS), which essentially means that the drug had been identified as one that would require special care in its prescription and use. As such, it was accompanied by special patient materials and warning labels not distributed with other drugs that are evaluated as posing less risk to patients.
• Early 2010 – FDA warned of possible problems with congestive heart failure in patients taking Multaq.
• Spring 2010 – FDA warned of a possible link between Multaq and a potentially fatal ventricular arrhythmia known as torsades de pointes.  Other drugs, such as Propulsid, have been recalled due to links to this same life-threatening arrhythmia as well as an electrical conduction problem in the heart known as “long QT syndrome.”
• September 2010 – FDA includes Multaq in a report entitled “Potential Signals of Serious Risks/New Safety Information Indentified by Adverse Event Reporting System (AERS) between July – September 2010,” which was part of a new initiative by the FDA to alert the public and medical community about potential, emerging drug-related safety issues.  This same report included some other drugs that remain under a cloud of suspicion and/or are the subject of current litigation efforts, including Epogen and Procrit (possible contamination with lamellae); Gemzar (liver toxicity); Keppra (linked to Stevens Johnson Syndrome and Toxic Epidermal Necrolysis); and Actos (rhabdomyolysis).
• January 14, 2011 – The FDA issued a Drug Safety Communication directed to patients and healthcare professionals regarding its receipt of numerous adverse event reports (also known as AERs) relating to liver toxicity, serious liver injuries, and acute liver failure requiring a liver transplant in patients taking Multaq.  At that time, it was estimated that more than 147,000 patients had taken the drug in the 18 months since it was approved.

Often, the potential for a new drug to cause liver failure is not identified until the drug is given to a large number of patients after the drug is placed on the market, and these patients, sadly, unknowingly serve as real world guinea pigs for new drugs that are tested on too few and under aggressively-controlled study protocol, such that study participants are often pulled from the pre-marketing clinical studies at the first signs of any toxicity and before it is possible to detect potential liver problems.  Drug-induced liver problems are a serious health issue in the United States, with more than 400 prescription and over-the-counter drugs being linked to hepatoxicity, with only a fraction of these drugs being recalled due to liver-related safety issues.

• February 11, 2011 – Drug warning label enhanced to include the risks of acute liver failure or hepatic toxicity.  The symptoms associated with acute liver failure include jaundice, abdominal pain, dark urine, itching, fever, malaise, anorexia, vomiting, and nausea.  Patients may also have abnormal blood tests slowing elevated liver enzymes.
• March 11, 2011 – Drug warning label further changed to discuss the potential for drug interactions, especially with warfarin (also known as Coumadin).
• June 21, 2011 – Multaq’s warning label was changed yet again to note that some patients who had taken the drug had developed serious pulmonary and respiratory problems, including interstitial lung disease, pneumonitis, and pulmonary fibrosis.  These serious lung problems had not been noted in the limited clinical trials completed to evaluate the safety of Multaq prior to FDA approval.
• July 21, 2011 – The FDA issued a “Drug Safety Communication” to doctors and patients regarding the increased risk of death and serious cardiovascular adverse events noted in an ongoing clinical trial involving patients taking Multaq (or dronedarone) for permanent atrial fibrillation (an indication for use of the drug that had not yet been approved by the FDA).  This clinical study is known as the Permanent Atrial Fibrillation Outcome Study Using Dronedarone on Top of Standard Therapy (PALLAS) Study.  The July of 2011 safety alert indicated that from July of 2009 through June of 2011 approximately 241,000 patients had ingested Multaq.  At that time, patients were urged to consult with their physicians regarding whether they should discontinue the medication, and were encouraged to report adverse events to the FDA and Sanofi-Aventis.  Physicians were also urged not to prescribe Multaq to patients with permanent atrial fibrillation, an off-label use of the drug. At that time, the FDA indicated that the data showing potential safety issues in the PALLAS clinical trial was preliminary, and that the Agency would be conducting a more thorough review to determine whether the same increased risk of cardiovascular death or serious heart-related side effects noted in study patients with permanent atrial fibrillation might also be seen in patients taking Multaq for paroxysmal or persistent atrial fibrillation or atrial flutter, conditions for which the drug had been approved by the FDA in 2009.
• August 5, 2011 – The Food & Drug Administrator and the manufacturer of Multaq updated the “Risk Evaluation and Mitigation Strategy (REMS)” plan, in order to further outline efforts to be undertaken to provide better information to patients and prescribing physicians in hopes of preventing future injuries and death to patients using Multaq.  In addition, patients who have suffered serious adverse reactions were urged to report them to the Food & Drug Administration at 1-800-FDA-1088 or at www.fda.gov/medwatch.  Patients have also been cautioned to consult with their physicians prior to discontinuing Multaq, as there are serious potential side effects if patients abruptly stop taking this medication.
• August 22, 2011 – The warning label was again modified to reflect that patients may experience changes in their kidney function while taking Multaq.  Adverse event reports have noted that patients experienced elevations in their creatinine and blood urea nitrogen (BUN) levels while taking Multaq.
• September 22, 2011 – The European Medicines Agency (EMA) Committee for Medicinal Products for Human Use (CHMP), the drug safety organization similar to the FDA that oversees drug safety in the European Union, met to discuss safety concerns over Multaq and whether the drug should continue to be prescribed in Europe.

In the past, the EMA has shown that it is more inclined to move swiftly to recall dangerous drugs and to put the welfare of patients before the interests of the pharmaceutical industry, unlike the FDA which has shown a tendency to move at a much slower pace while it studies safety issues relating to drugs (and, sadly, to give the drug manufacturers a few more months or years for last-ditch efforts to peddle unsafe pills).  The EMA committee recommended that use of Multaq be limited in light of evidence that the drug was associated with serious adverse effects on the liver, heart, and lungs.

Meanwhile, patients in the United States are faced, yet again, with a difficult situation.  So, what should Multaq patients do?  Patients should consult with their physician now and on a regular basis to determine whether continued use of Multaq, in the face of growing safety concerns, is warranted given their particular medical history and personal risk factors.

Patients should also urge the drug manufacturers and the FDA to be more proactive in removing dangerous drugs from the market rather than continuing to issue press releases and revised warning labels which, obviously, are failing to protect patients from drug-induced injuries.

For additional resources related to Multaq, please visit these sites:

Manufacturer’s web site

Medication Guide for Patients

REMS

July 2009 label

February 2011 label

March 2011 label

June 2011 label

August 2011 label

FDA summary memo regarding review of the new drug application for Multaq

FDA drug approval package

7/21/2011 Safety Alert

1/14/2011 Safety Alert

January 2011 – FDA podcast on liver toxicity

As depicted in the following video, over the years, cardiologists have relied upon invasive catheterization to diagnose cardiac-related blood flow problems and muscle wall damage. However, placing a catheter into blood vessels and guiding it into the heart is technique-sensitive, and is far more invasive and less diagnostic than the use of Positron Emission Tomography (PET).

This is true because instead of using a mechanical, wire-like catheter, cardiologists can inject a less intrusive “Rubidium-82 saline liquid” into patients’ blood vessels  The short span radioactive liquid (having a very short 76 second half life) then combines with the blood that usually flows through the blood vessels. The Rubidium-82 liquid, also called a tracer, acts just like potassium. Rubidium-82 substitutes itself in place of potassium in the cells.

If the physician injects a potassium analogue tracer into a patient, the patient’s heart muscle cells will absorb the tracer. Note that blood vessels carry the tracer to the heart muscle, but while the tracer disappears in the blood, it collects in the heart muscle, providing a sharp contrast when viewed via a PET scanner that can photograph the emitting radiation.

Several minutes after the Rubidium-82 tracer injection, a PET image will show a concentrated, retained tracer in the heart, which contrasts with the low activity in the blood (because newly circulating blood is carrying away the excess tracer).

Since Rubidium-82 has a relatively short, 76 second half-life, after six half-lives (450 seconds or 7.5 minutes), investigators treat the tracer as completely decayed  – because only a mere 1.6% of original radioactivity remains. This brevity of activity means that the tracer cannot be stored and transported between facilities. Instead, it must be produced on-site.

The usual way to produce tracers is by using an expensive cyclotron. Because the cyclotron is expensive and cumbersome, researchers investigated alternative ways to produce tracers with less expensive equipment that could be used on-site in the offices of cardiologists or other healthcare providers. The Cardiogen-82 Strontium-82 to Rubidium-82 generator, which General Electric manufactures and distributes for Bracco Diagnostics, Inc., is a relatively inexpensive piece of equipment that can produce Rubidium-82 from Strontium-82 (which has a longer half-life of 24 days). Strontium-82 is produced from Strontium-85 (having a half-life of about 65 days). Given the much longer half-lives, strontium isotopes would be too toxic for use as tracers in humans.

The CardioGen-82 generator employs a long tin oxide tube that contains the more toxic Strontium-82 (parent), and normal saline is pumped through the tin oxide tube, which results in the manufacture of the less toxic Rubidium-82 tracer. Of course, it is paramount that physicians prevent an occurrence called “breakthrough,” which happens when Strontium-82 is carried along with Rubidium-82 in the tracer liquid in larger than permissible amounts. Injecting Strontium along with Rubidium into a patient increases the risks of radiation poisoning.

The relatively short half-life of Rubidium-82 is both an advantage and a disadvantage. On the positive side, quick decay means shorter patient exposure to radiation. And, physicians can perform repeated PET scans every 10 minutes, because the radiation from the previous dose has disappeared by that time. However, fast decay shortens the maximum scan time and reduces the quality of the scans. That is the reason why on-site Rubidium-82 tracer manufacture and direct tracer injection into a patient, within a really brief period, is so necessary.

The information, above, makes it clear that both catheterization and Rubidium PET scanning have diagnostic pros and cons. While Rubidium PET is less mechanically invasive, and more diagnostic than catheterization, Rubidium PET is, nonetheless, invasive because of the use of radiation in patients and the complexity of technique required in order to use the product safely. If Strontium-82 were to break through during a procedure, it could be disastrous to a patient.