The Bitter Pill

The Official Blog of UNITE – uniteforlife.org

April 2007 Big Pharma Litigation Update – Drugs – Part I

Evelyn Pringle April 5, 2007

For the last two decades, illegal drug marketing schemes have paid off well for Big Pharma. However, as the old saying goes, all good things must come to an end, and every major drug company is currently involved in massive litigation.

Some companies are facing thousands of lawsuits with a common complaint that the drug maker deliberately concealed the side effects of their products while illegally promoting the drugs for off-label use.

Off-label refers to prescribing drugs to treat conditions other than those approved by the FDA and listed on the label. It can include prescribing drugs to unapproved populations, such as children or the elderly, or in higher doses than specified on the label.

It is illegal for drug companies to promote a drug for off-label uses, but doctors are allowed to prescribe a drug for any use they choose. Almost without exception, the lawsuits currently pending accuse the pharmaceutical companies of influencing doctors to prescribe the product for unapproved uses.

On August 18, 2006, Bloomberg News reported that Wyeth has accumulated more than 175,000 lawsuits since the Fen-Phen diet combination was removed from the market after studies revealed that the drugs caused heart valve damage, and primary pulmonary hypertension, or PPH, a life-threatening lung disorder. All total, Wyeth has set aside more than $21 billion to cover legal costs and settlements since the drugs were withdrawn, according to Reuters on May 24, 2006.

There was a national class-action settlement involving claims for heart valve damage, but it did not include claims for PPH which are proving to be costly. In one 2004 case alone, a Texas jury awarded over $1 billion to the family of a woman who died of PPH after taking Fen-Phen for about two years, including $113.4 million in compensatory damages and $900 million in punitive damages, according to Wyeth’s 2005 Annual Report. The case was later settled for an undisclosed amount.

PPH is a life-threatening condition that can require a heart-lung transplant. According to the FDA, PPH “results in death in about 40% of affected individuals within 4 years.”

The Fen-Phen combination was never FDA approved for any use, which means every prescription was off-label. Patients were able to get Fen-Phen on the internet, and Jenny Craig and Nutri-System set up weight-loss programs where doctors would prescribe the drugs to customers.

And there appears to be no end in sight for Fen-Phen lawsuits. On December 5, 2006, five more women who took the drugs in 1996 and 1997, filed lawsuits against Wyeth after being diagnosed with PPH. When it comes to liability, a plaintiff’s attorney, Paul Rheingold, in “Fen-Phen and Redux: A Tale of Two Drugs,” says, “there is blame enough to go around.”

The doctors who set up store-front Fen-Phen clinics and prescribed the drugs are obvious culprits, he says, and so are drug companies that profited financially from the fad and may have neglected to pass on information about deadly side effects.

On August 18, 2006, Bloomberg reported that Wyeth was facing 5,000 lawsuits over the menopause drug, Prempro, alleging that Wyeth misled the plaintiffs through deceptive marketing about the cancer risks associated with estrogen and progestin. As many as 6 million women took Prempro before it was linked to cancer in a 2002 study.

Financial analysts are predicting that, Merck in the end, will pay out as much as $50 billion for Vioxx litigation. On March 12, 2007, Reuters reported that a New Jersey jury found the drug was responsible for a plaintiff’s heart attack and awarded $20 million in damages.

According to Reuters, the jury also found that Merck committed consumer fraud by making misrepresentations concerning the heart risks, and intentionally concealing safety information from doctors prior to the plaintiff’s heart attack.

A large number of lawsuits have also been filed against Merck, over the osteoporosis drug Fosamax, and against Johnson and Johnson, over the Ortho-Evra birth control patch. The plaintiff’s allege that Fosamax causes jaw-bone death (OJN) and that the patch causes blood clots, which in turn lead to strokes.

Legal experts predict causation in cases involving Fosamax and the Ortho patch will be easy to prove because the plaintiffs have what is referred to as a “signature disease,” meaning a condition easily tied to the drug because it is rare.

The jaw-bone death occurring in people taking Fosamax is extremely uncommon. Kenneth Hargreaves of the University of Texas, noted the increasing cases in the April 3, 2006 LA Times. “We’ve uncovered about 1,000 patients in the past six to nine months alone,” he said, “so the magnitude of the problem is just starting to be recognized.”

FDA approved in 1995, Fosamax is a relatively new drug, and unreported cases may be higher than expected because doctors may attribute the pain caused by ONJ to osteoporosis, according to Diane Wysowski of the FDA’s Office of Drug Safety.

Dr Salvatore Ruggiero, an oral surgeon and one of the first doctors to notice the rise in ONJ in 2001, told the Times, “Even though the chances of getting this are small, considering there are 23 million women taking this drug, we could be talking about a significant number of people.”

The same goes for the Ortho patch. Blood clots seldom develop in young women of childbearing age. And legal experts say, for that reason, many Ortho patch lawsuits have already ended in confidential settlements with hardly a peep in the mainstream press, and J&J has made it clear to other plaintiffs’ attorneys that the company is willing to cut a deal.

Experts predict that many more lawsuits will be filed because there are thousands of young patch victims who are still unaware that the patch caused the health problems. In 2005 alone, more than 9.4 million prescriptions were written for the Ortho patch, according to IMS Health, an industry-tracking firm.

The FDA says it has received about 9,000 reports of adverse events related to the patch, but the agency also acknowledges that only between 1% and 10% of adverse events are ever get reported.

There are over a hundred more lawsuits filed against J&J involving the Duragesic pain patch. The device is supposed to deliver controlled doses of fentanyl, a drug so powerful that high doses can turn off the respiratory center in the brain.

On July 8, 2006, the Associated Press reported that a Houston jury had awarded $772,500 to the daughter of a woman who died after a leak on the patch increased the dose of the painkiller, and the jury found J&J negligent in the way the patch was made.

Another fentanyl product that legal experts say will bring a wave of lawsuits in the next couple of years, is Cephalon’s painkilling lollipop, Actiq. The product was only approved to treat cancer patients in chronic pain who are already on an opioid drug, because life-threatening conditions can occur at any dose in patients without a built-up tolerance for opioids. But a recent study by Prime Therapeutics found Actiq is being prescribed off-label nearly 90% of the time.

Fentanyl is reportedly 80 times stronger than morphine, and is a Schedule II narcotic drug, in the same category as cocaine, opium, methamphetamine and methadone, a class known to have the highest potential for abuse and overdose.

In 2004, there were an estimated 8,000 emergency-room visits for fentanyl overdoses, according the US Substance Abuse and Mental Health Services Administration. Overdose can result in sudden death through respiratory arrest, cardiac arrest, severe respiratory depression, cardiovascular collapse or severe anaphylactic reaction, according to the agency. As of November 16, 2006, there were 653 deaths confirmed in the US since 2005.

In November 2006, the Wall Street Journal, said evidence obtained in litigation showed Cephalon had set high sales quotas for its sales representatives that could not be reached without promoting Actiq off-label.

Internal company documents show sales reps were regularly sent to doctors who treated no cancer patients, with free coupons for doctors to pass out to patients. According to the Journal, Dr Stephen Leighton, a general practitioner with only 3 cancer patients at any given time, said a Cephalon saleswoman stop by once a month and gave him about 60 to 70 coupons to pass out to patients for 6 Actiq lollipops.

He told the Journal that the coupons led him to try the drug for migraines and back pain and said he prescribes Actiq 15 to 20 times a month to patients who do not have cancer.

According to the November 3, 2006, report in the Journal, Actiq sales increased from $15 million in 2000, to more than $400 million today.

The consequences of the off-label prescribing of this product are far reaching. On January 22, 2006, the Free Press reported that the wife of a minister, a former schoolteacher and mother of three, was charged with involuntary manslaughter because she gave Actiq to a friend for a migraine, and the friend died of a drug overdose.

More lawsuits are sure to be filed against Eli Lilly since secret internal documents obtained in litigation by attorney, Jim Gottstein, from Dr David Egilman, an expert in previous Zyprexa litigation, prove that the company concealed Zyprexa’s link to severe weight gain, high blood sugar, and diabetes for a decade, while Lilly promoted the drug for so many off-label uses that more than 20 million people have taken Zyprexa.

To date, Eli Lilly has spent well over $1 billion to settle about 26,000 Zyprexa lawsuits, with still more litigants waiting in line. Zyprexa has been linked to serious side effects, including diabetes, hyperglycemia and pancreatitis.

On January 14, 2005, a class-action lawsuit was filed in Canada with claims that Lilly also withheld information on the safety of Prozac. The plaintiffs allege that the reason Lilly failed to disclose the documents was because they showed a drastic increase in suicide attempts and other violent acts in patients taking Prozac, when compared to patients taking 4 other drugs.

All through the 1990s, Lilly swore that Prozac did not increase the risk of suicide or violence, while the company was quietly settling lawsuits out of court which made it possible to keep the incriminating evidence hidden with court orders, just as it has been doing with Zyprexa until the secret documents showed up in the press in December 2006.

Similar lawsuits are being filed against AstraZeneca over its antipsychotic drug, Seroquel, which reportedly has been used by more than 16 million people since it came on the market in 1997. The plaintiffs in those cases also claim that Astra downplayed the diabetes risks and concealed safety information.

Filed under: 2007, AstraZeneca, Cephalon, Eli Lilly, fen-phen, fentanyl, Fosamax, Johnson and Johnson, Merck, ONJ, Ortho, patch, PPHN, Seroquel, settlement, Vioxx, Wyeth, Zyprexa

Experts Alarmed by Rising Cases of Fosamax Jaw Bone Death

Evelyn Pringle October 25, 2006

Dentists and oral surgeons are becoming increasingly worried about the rising number of patients they are seeing with osteonecrosis (ONJ).

ONJ is a painful, disfiguring, debilitating condition that essentially rots the jawbone, as a result of millions of Americans taking the relatively new class of osteoporosis medications.

The drugs belong to a class of medications known as bisphosphonates, and the most popular by far is Merck’s Fosamax, which has been on the market for about a decade.

Fosamax is Merck’s second best selling drug, with revenue last year of $3.2 billion. According to the market research firm, Verispan, 4.2 million prescriptions were written for Fosamax in 2005.

Other drug makers market lesser known bisphosphonates, Procter & Gamble together with Sanofi-Aventis, markets Actonel, which gained FDA approval in 2000, and GlaxoSmithKline and Roche market Boniva which became available last year.

A small number of patients also receive intravenous versions of the bisphosphonates, Zometa and Aredia, as part of cancer treatment.

Critics say the drastic increase in the sale of these drugs over the past several years, to mostly women who are too young to even need them, is due to massive advertising campaigns aimed at consumers in their 40s and early 50s, with the intent that the newly recruited customers will take the drugs for life.

According to the market research firm, TNS Media Intelligence, in 2005 the drug makers combined spent more than $174 million advertising bisphosphonates, up from $54.8 million in 2003, before Boniva was added to the mix.

In treating osteoporosis, according to the August 3, 2006 Dallas Morning News:

“Bisphosphonates work by targeting the cells that constantly remodel internal bone structure. The engines of this turnover are cells called osteoclasts that clear away old bone, and cells called osteoblasts that form new bone in its place. Bisphosphonates slow the work of osteoclasts, but by doing so, also affect osteoblasts because the two work in tandem.”

About 5 years ago, dental professionals first began suspecting a link between bisphosphonates and ONJ, and in 2004, the FDA acknowledged that it had received reports of the condition, mainly in cancer patients receiving the drugs intravenously and recommended that the professional product labeling for the drugs be revised to warn of the possibility of ONJ, but the changes to the labeling were not made until 2005.

Earlier this year, the American Association of Endodontists advised dental surgeons to consider patients on bisphosphonates to be at risk for ONJ.

Fosamax ONJ lawsuitBecause many patients have now been on the drugs for several years, and because more and more prescriptions are being written for the drugs each year, experts say a high number of cases of patients with ONJ are expected to surface over the next few years.

And even though the warnings about the risk of ONJ are now being publicized, the problem for people who have been taking the drugs for years is that even if they quit, bisphosphonates remain in the bones indefinitely.

In addition to causing unbearable pain that often cannot be relieved with ordinary painkillers, ONJ can lead to the loosening of teeth and loss of dental implants, and a host of other problems such as difficulty eating, infections of the face and neck, halitosis, and headaches.

Experts are uncertain why the use of these drugs leads to ONJ. On June 15, 2006, Dr Brian Alpert, a maxillofacial surgeon at the University of Louisville School of Dentistry, told the Louisville Courier-Journal that the bisphosphonate may shut down the production of the osteoclasts, making it difficult for the bone to respond and recover if an infection sets in. In the mouth, where bacteria can actually reach the bone, he says, the drug makes it impossible to fight that bacteria.

A February 2006, study in the Journal of Obstetrics & Gynecology and Reproductive Biology, found that Fosamax caused significant DNA damage in white blood cells in 32 postmenopausal women over a 12-month period. White blood cells are key components of the body’s immune system so critics say that even the possibility of such an effect is troubling.

Whatever the cause, experts warn that there is no cure and that the cases of ONJ are on the rise. Dr Alpert told the Courier-Journal that in 36 years of practice he has seen fewer than 5 cases but that he has now seen seven cases in the course of one year.

“What we have seen and heard from health-care givers is that more and more people are showing up with milder forms, so the true incidence rate now is anybody’s guess,” Dr John Kalmar, an Ohio State University oral pathologist and author of a May 2006 review article in Annals of Internal Medicine, told the Philadelphia Inquirer on June 26, 2006.

Studies have also shown that over time, Fosamax may not accomplish its intended goal of preventing fractures, because experts are finding that the drug may indeed increase bone density but the bones of patients on Fosamax are more brittle and thus more likely to fracture.

In April 2006 the first Fosamax class action lawsuit against Merck was filed in Florida, claiming not only that the company knew about the ONJ risk but also that it refused to study the matter further and ignored requests by the FDA in 2004 to warn consumers about the condition.

According to the October 6, 2006 Chicago Tribune, some 15 class action lawsuits against Merck have been filed in the US. “This is a once-in-a-decade case,” Pensacola, Florida, attorney Tim O’Brien, who specializes in pharma litigation and filed the first class action, told the Tribune.

“This is so rare,” he says, “that you can actually trace back the injury to the cause of the injury.”

“It’s a signature injury,” he told the Tribune.

In one of the latest public warnings, on October 11, 2006, the Pennsylvania Dental Association issued a press release to inform the public about ONJ and said that over “a thousand cases of ONJ had been reported in patients undergoing bisphosphonate treatment.”

The press release referred to one of the largest reports on bisphosphonate-associated ONJ, in an article by Dr Salvatore Ruggiero, chief of the Division of Oral and Maxillofacial Surgery at the Long Island Jewish Medical Center.

“The patients represented in this series of case reports,” the group wrote, “were preponderantly female and typically presented with bone pain, nonhealing extraction sockets or exposed bone.”

“Most cases of osteonecrosis of the jaw associated with bisphosphonates have been diagnosed after dental procedures such as tooth extraction,” the press release said, “however, the condition also can occur spontaneously,” it warned.

“Because invasive dental procedures, such as gum surgery, extractions, or other surgery that affects the bone, can worsen bisphosphonate-associated oral conditions,” the Dental Association advised, “anyone that has taken bisphosphonates should advise his or her dentist.”

“It is especially vital that patients report any symptoms or oral changes to their physician or dentist,” said Dr Sean Boynes, a PDA member and assistant professor at the University of Pittsburgh School of Dental Medicine.

“In addition,” he added, “patients who have begun bisphosphonate therapy should have consistently scheduled dental hygiene appointments.”

“The regularity of these evaluations is usually at the judgment of the treating physician or dentist,” he wrote, “but could occur as often as every 3 months.”

After being diagnosed with and researching ONJ, Dr Beverly Hurwitz, a Salt Lake City doctor who treats chronic pain, told the Salt Lake Tribune on June 26, 2006, that she sent out about 50 warning letters to dentists and oral surgeons in Utah. But as she only received a few replies, she says she is worried that dentists and the public are still uninformed about the condition.

“I know there are millions of women who are on these drugs who need a root canal or other work,” Dr Hurwitz told the Tribune. “There are probably thousands of people who have this and haven’t been diagnosed.”

“People say this is a rare condition,” she states, “but it’s only rare because it hasn’t been identified.”

Dr Patrick Brain, an oral surgeon in Sandy, Utah, says more dentists and oral surgeons are becoming educated about the link between Fosamax and ONJ. “It’s a big problem, and it’s becoming more pervasive,” he told the Tribune.

In the end, neither the warnings nor the lawsuits have slowed the sales of Fosamax. According to Merck’s latest SEC filing, global sales for Fosamax were $771 million for the third quarter of 2006, representing a decrease of only 1% compared to third quarter 2005, and US sales for the quarter increased 7%. Overall, the company reported global sales for the first nine months of $2.3 billion, and Fosamax products remain the most prescribed drugs worldwide, Merck says, for the treatment of postmenopausal, male and glucocorticoid-induced osteoporosis.

Filed under: 2006, Fosamax, Merck, ONJ

Cases of Fosamax Jaw Bone Damage Continue To Rise

Evelyn Pringle October 12, 2006

An article in the October 2006, “Current Opinions in Orthopaedics,” by Dr Catherine Van Poznak, assistant professor of internal medicine at the University of Michigan Medical School, reports that 10% of cancer patients taking Fosamax, or other drugs known as bisphosphonates, have developed osteonecrosis of the jaw (ONJ).

An April 4, 2006 United Press International poll found that more than 2,400 patients who were taking the injected form of bisphosphonate had suffered bone damage to their jaws since 2001. Other bisphosphonates include Aredia, Zometa, Actonel and Bondronat.

ONJ, also called jawbone death, is a disfiguring, debilitating and non-reversible condition marked by exposed and deteriorating jawbone. The disease kills tissue within the jawbone causing pain, swelling, loose teeth, and inflammation. The condition may take years to develop and usually becomes known following a dental extraction, implant or other procedure when the wound does not heal properly.

Fosamax is the world’s top selling bisphosphonate, and is prescribed to prevent osteoporosis, but experts now say that the ONJ side effect directly contradicts its intended purpose.

In the name of profits, critics say Fosamax was over promoted by the pharmaceutical giant Merck, as a life-long treatment for osteoporosis with individuals, especially women, too young to be at risk of developing bone problems.

“The pharmaceutical industry has every desire that a patient who starts on a bisphosphonate would take it for life,” said Dr Robert Gagel, of the Anderson Cancer Center in Houston, to Gina Kolata of the New York Times. “The bone community, of which I am a member,” he noted, “has always been a bit suspicious of that viewpoint.”

The injuries showing up now, critics say, are the result the massive marketing of a class of drug to relatively young persons, who in the majority of cases, did not need them to begin with.

In addition to the tens of millions of dollars spent on public advertising campaigns, Merck relied heavily on industry backed front groups to promote Fosamax and the National Osteoporosis Foundation (NOF), proved most helpful in first promoting the disease in younger women, followed by the promotion of the “cure.”

Merck is a major donor to this organization and is listed in its Annual Report, albeit minus the amount of money that the company donates each and every year.

NOF serves as a major funnel when it comes to promotional campaigns. In 2004 alone, the group’s Annual Report listed revenues of more than $6 million.

The NOF’s web site promotes Fosamax but does not warn about ONJ. Consumer who look to these types of organizations for unbiased information about pharmaceutical products are unaware of their financial support from the drug companies that manufacture the drugs they promote.

Critics say that needs to change now that front groups are playing a much larger role in the drug approval process. For instance, when a drug is up for review before the FDA’s Drug Safety and Risk Management Advisory Committee, members of these groups sign up to testify to praise the safety and efficacy of a drug without disclosing their financial support from the sponsoring drug company.

Wake Forest University health sciences researcher, Dr Curt Furberg, sat on the FDA Advisory Committee for 2 terms and says he frequently heard testimony from members of these groups.

Unlike other speakers, he told the Washington Post on February 7, 2006, spokesmen for the groups do not identify their potential conflicts of interest at the Committee meetings and often sound like they represent drug companies.

Typically, he told the Post, the groups will present a patient to testify about how a drug with emerging safety problems changed his life for the better.

“I don’t doubt that,” Dr Furberg said. “But it is interesting that there was no widow at the hearing who says, ‘My husband took these drugs and he had a heart attack and died and it changed my life.’

“It’s not balanced,” he says. “My sense it that one point of view is missing – the bad news.”

Merck’s marketing tactics for Fosamax have been extremely successful. The company recorded sales of $3.2 billion from Fosamax in 2005, when more 22 million prescriptions were written in the US alone, according to the pharmaceutical tracking firm IMS Health.

These high sales figures peaked during the same year that the FDA asked Merck to warn patients about the risk of developing ONJ.

But the warnings apparently had little impact. On May 15, 2006, Business Week Online, reported that the “global osteoporosis market is at $6 billion in annual sales today, and with a rapidly graying population, it’s growing 25% a year.”

There is no treatment for ONJ and therefore, according to Dr Van Poznak, the focus of medical professionals must be on preventing the condition or alleviating the symptoms.

“We don’t know how to predict who will develop ONJ or who is most at risk,” she said.

Critics say Merck knew about ONJ and failed to warn medical professionals and consumers for years. “Merck became aware of this problem in early 2001 when the first reports starting coming in,” says Attorney Cory Rosenbaum, a partner in the Rosenbaum Faria law firm.

“They waited until September 2004 to issue a warning to health care professionals, and they didn’t post any warnings on their labels until 2005,” he said in a September 24, 2006 press release.

Dr Gregory Lutcavage, an oral and facial reconstructive surgeon with Eastern Carolina Oral and Maxillofacial Surgery Associates, told the Goldsboro News Argus on July 24, 2006, that the warning process has been very frustrating, especially witnessing patients suffering and drug companies delaying going public about the risks and ramification.

“One drug company did not come out with the update to their circular until about three or four months ago,” he said. “We were seeing this three years ago.

“I said to my partners several years ago,” Dr Lucavage told News Argus, “this is a class action suit waiting to happen.”

And the inevitable event he mentioned is indeed happening. One of several class action lawsuits was filed in Florida in April 2006, accusing Merck of failing to warn medial professionals and patients about the risk of ONJ associated with Fosamax.

“We’re getting people calling every day,” Attorney, Gary Wilson, in Minneapolis told the LA Times on July 11, 2006. Mr Wilson said his firm will probably file about 20 cases in the coming months.

Florida attorney, Timothy O’Brien, told the Times that he has filed 30 Fosamax lawsuits and expects to file at least 300 more over the next few months involving Fosamax and Actonel.

The lawsuits claim that Merck aggressively marketed Fosamax as safe and effective, despite knowing about the drug’s potential to cause a disease in which a patient’s jawbone rots and dies.

Although experts agree that there is no cure for ONJ, for the purpose of prevention, the American Dental Association recommends that patients be sure to inform their dentist if they are taking a bisphosphonate before any dental work is performed.

In a warning to professionals, the American Association of Endodontists, a group representative of dental care providers who specialize in root canal surgery, issued a position statement in March 2006 that said, “until further information becomes available, the AAE recommends that all patients taking bisphosphonates be considered at some risk.”

“While bisphosphonates support the buildup of bone in areas weakened by disease,” the AAE told its members, “as a side effect of treatment, patients may experience the opposite in their lower and upper jawbones.”

Fosamax is a relatively new drug, FDA approved in 1995, so the long-term risk of ONJ is unknown, experts say. Unreported cases may be higher than expected, according to Diane Wysowski of the FDA’s Office of Drug Safety, because doctors may attribute the pain caused by ONJ to osteoporosis.

Kenneth Hargreaves, chair of the endodontics department at the University of Texas, noted the rapidly increasing cases in the April 3, 2006 LA Times. “We’ve uncovered about 1,000 patients in the past six to nine months alone,” he said, “so the magnitude of the problem is just starting to be recognized.”

However, because only between 1% and 10% of adverse events are ever reported to the FDA, experts say the number of cases of ONJ is bound to be much higher.

Dr Salvatore Ruggiero, an oral surgeon at Long Island Jewish Medical Center, was one of the first medical professionals to notice the rise in ONJ patients in 2001. “We never saw this before in the jaw” except in patients who had received radiation therapy to that part of the face, Dr Ruggiero told USA Today on May 13, 2005. “It just never existed.”

On April 14, 2006, he told the Wall Street Journal that of the 155 cases of ONJ that he has come across, 22 involve patients who were taking Fosamax and other oral bisphosphonates and some of the patients took Fosamax for seven or eight years. “With the oral drugs like Fosamax, exposure time is the key,” Dr Ruggiero told the WSJ.

He is concerned about the millions of women taking bisphosphonates to treat osteoporosis long term. “Risks increase,” he explained, “the longer you’re on the drugs, and it can take years for the complication to manifest itself.”

“Even though the chances of getting this are small,” he told the Times on April 3, 2006, “considering there are 23 million women taking this drug, we could be talking about a significant number of people.”

Experts agree that stopping the use of Fosamax will not necessarily be helpful for persons who have already been on the drug for several years because the build-up of Fosamax in the body is cumulative and the drug can remain in the bones indefinitely.

There are signs that medical professionals are becoming more aware of ONJ. A study quoted in the September 14, 2006, Star Ledger, by health care marketing research group, Manhattan Research, found that in the first half of 2006, an increasing number of doctors were visiting brand name drug web sites seeking information about dosages and side effects of drugs, and the top 10 sites visited included Fosamax.

Experts recommend that anyone who has been on Fosamax for three or more years should get a thorough examination of the jaw from an oral surgeon before having any extractions or implant work done.

Filed under: 2006, Fosamax, Merck, ONJ, settlement

Cases Against Merck for Fosamax Jaw Bone Damage Growing

Evelyn Pringle June 13, 2006

Scranton, PA: Medical professionals need to recognize that Fosamax has only been on the market for a little over a decade and other bisphosphonates for even less time. The injuries showing up now are often the result of massive marketing of this class of drugs to relatively young persons who in many cases did not need them to begin with.

Over the last 10 years, tens of millions of people have taken Fosamax believing it would prevent bone deterioration. The drug seemed safe enough at first but in recent years it has been linked to a serious disease that causes death to the bone in the jaw, called osteonecrosis of the jaw (ONJ). The disease is an extremely serious condition and symptoms include, but are not limited to:

Pain, swelling, or infection of the gums
Loosening of teeth
Poor healing of the gums
Numbness or the feeling of heaviness in the jaw
Partial or complete loss of the jaw bone

This is another case where the risks of a drug are high while the efficacy is questionable. Experts now say that Fosamax may improve bone density, but when it comes to fracture prevention, its benefits are minimal. In fact, some say that if taken for more than 10 years, the drug can actually make bones more brittle and increase the risk of fracture.

And stopping the drug is not the answer because Fosamax remains in the body for years after patients stop taking it. Some dentists are even refusing to treat patients who are on this class of drugs, fearful that dental work such as a tooth extraction may bring on a case of ONJ.

Fosamax has been on the market since 1995. Actonel came on the market in 2001 and Boniva arrived last year. As more Fosamax was sold and more bisphosphonates came on the market, more and more injuries showed up. Experts say to just wait and see what happens over the next 10 years.

Fosamax is the world’s top-selling bisphosphonate. It is Merck’s second best-selling drug, with sales in 2005 of $3.2 billion, according to the Associated Press. In the US alone, more than 22 million prescriptions were written last year, according to the drug research firm IMS Health.

After its launch, Actonel became the fastest product in Proctor & Gamble’s history to reach $1 billion in sales.

Boniva was developed by Hoffman-LaRoche, and is co-marketed with GlaxoSmithKline and can be taken once a month while its competitors must be taken weekly.

Novartis’s markets Aredia and Zometa, the two intravenous versions used in chemotherapy. Nearly 3 million cancer patients have been treated with intravenous versions of the drugs.

None of these greedy drug makers are going admit that these drugs cause ONJ and throw in the towel as long a $3 billion pot is up for grabs in the US alone. According to Business Week Online, on May 15, 2006, the “global osteoporosis market is at $6 billion in annual sales today, and with a rapidly graying population, it’s growing 25% a year.”

This class of drugs represents an infinite goldmine for their makers. Advertising to women in their 40s and on up to death, has created a massive market.

“The pharmaceutical industry has every desire that a patient who starts on a bisphosphonate would take it for life,” said Dr. Robert Gagel of the MD Anderson Cancer Center in Houston to Gina Kolata of the New York Times. “The bone community, of which I am a member, has always been a bit suspicious of that viewpoint,” he noted.

Fighting over this goldmine has got the giant drug makers taking pot-shots at each other. Amgen’s osteoporosis drug, Denosumab, is getting ready to come on the market in the next few years, and Amgen is already paving the way to push Fosamax’s market share lower.

“At an analyst meeting earlier this year,” according to Business Week, Amgen “presented research showing that 70% of patients taking top-selling osteoporosis drugs such as Merck’s Fosamax drop out in the first year of treatment because of heartburn, ulcers, and other side effects.”

Roger Perlmutter, Amgen’s executive vice-president for research and development, pointed out the concerns that Fosamax may cause ONJ.

Perlmutter says that Denosumab mimics the body’s natural mechanism for blocking the formation of bone-destroying cells while Fosamax slows down the activity of cells that have already formed.

Amgen’s drug, he notes, needs to be taken only twice a year verses once a week for Fosamax.

“What’s more, Amgen’s drug doesn’t bury itself deep in the bone for years the way Fosamax does,” Perlmutter told Business Week.

For all those reasons, he said, “we think there would be much less risk of adverse effects.”

In the US District Court for the Southern District of New York, Procter & Gamble has asked a judge to force Hoffman-LaRoche to withdraw some of its advertising and stop making some of its claims about Boniva.

P&G alleges that Hoffman has engaged in “an orchestrated, intentional campaign” to tell doctors and consumers that Boniva is just as effective as Actonel and Fosamax, according to a June 2, 2006 article by the Associated Press.

In turn, Hoffman is accusing P&G of falsely telling doctors that they could be sued for malpractice if they prescribed Boniva, and of making efficacy claims not supported by P&G experts, and submitting consumer research with forged signatures to the court.

Merck is also battling to retain its share of the market. On May 13, 2006, Bloomberg News reported that Merck is accusing generic-drug company Teva Pharmaceutical Industries of committing fraud in its successful effort to invalidate Merck’s patent on the once-a-week version of Fosamax.

In a lawsuit filed in Delaware, Bloomberg says, Merck is trying to reverse an appeals court decision that threw out its patent on the weekly dose form of Fosamax and wiped out 10 years of potential sales for Merck and opened the door to generic competition when the drug on the main compound expires in February 2008.

Merck has previously failed to get the Federal Circuit to reconsider the decision, and the US Supreme Court has refused to consider the appeal. The new lawsuit cites new evidence that the company claims surfaced in April 2006.

And although Merck is already in the battle of the century defending Vioxx lawsuits, the company is now facing a full frontal attack from Fosamax lawsuits. In April 2006, Linda Secrest filed a lawsuit in federal court in Florida, accusing Merck of failing to warn doctors and patients that Fosamax could hamper blood flow to the jaw.

The lawsuit alleges Secrest began taking Fosamax in 2000, and was diagnosed with jawbone death in 2005 and that the condition is irreversible.

The complaint seeks to represent more than 10 million Fosamax users and the lawsuit is the second of about 200 lawsuits that Secrest’s attorney, Tim O’Brien, told Bloomberg News on April 11, 2006, that he plans to file.

Admittedly, Fosamax won’t be another Vioxx because Vioxx as a pain killer, was prescribed far more often than Fosamax. But make no mistake, tens of thousands of patients have already been injured over the past decade and the number of lawsuits will be substantial. Experts predict that up to 10% of people who received bisphosphonates may be effected by ONJ.

P&G and Sanofi-Aventis have also been hit with lawsuits but not to the extent of Merck simply because their product was on the market for a much shorter time. Hoffman and GSM have reportedly not been sued over Boniva – yet.

A study cited on April 4, 2006, by United Press International, found more than 2,400 patients who were taking the injected form of bisphosphonate had suffered bone damage to their jaws since 2001, and an additional 120 patients taking the oral form of the drug had been stricken.

Dentists and oral surgeons first began noticing the link between jaw bone death and bisphosphonates 5 years ago, and at first thought that it was only the intravenous versions of the drugs administered to cancer patients that posed a risk. But over the past few years, they discovered that oral bisphosphonates also cause ONJ when taken over a long period of time.

In fact, in March 2006, the American Association of Endodontists issued a position statement recommending that oral surgeons check to see if patients are on bisphosphonates and consider those that are to be at risk for ONJ.

Endodontists specialize in root-canal surgery and warn that “until further information becomes available, the AAE recommends that all patients taking bisphosphonates be considered at some risk.”

“While bisphosphonates support the buildup of bone in areas weakened by disease,” the group says, “as a side effect of treatment, patients may experience the opposite in their lower and upper jawbones.”

The debate over ONJ first gained momentum in 2003 when Dr Robert Marx, chief of oral and maxillofacial surgery at the University of Miami, wrote a paper in the Journal of Oral Maxillofacial Surgery and referred to osteonecrosis of the jaw as “a growing epidemic.”

Dr Marx reported 36 patients who had experienced “painful bone exposure,” and “were unresponsive to surgical or medical treatments.”

The 36 patients had two things in common. They all had cancer and they were all treated with bisphosphonates.

A little over a year ago, on May 13, 2005, Dr Marx told USA Today that he was aware of at least 40 or 50 cases of ONJ nationwide in patients who had taken Fosamax.

Dr Salvatore Ruggiero, chief of oral surgery at the Long Island Jewish Medical Center in New York, quoted in the Wall Street Journal on April 14, 2006, said that of the 155 ONJ cases he had come across, 22 patients were taking Fosamax or another oral bisphosphonate. Some of these patients took Fosamax for seven or eight years, he said.

“With the oral drugs like Fosamax, exposure time is the key,” Dr Ruggiero told the WSJ.

Dr Ruggiero says he first saw patients with breast cancer or multiple myeloma who arrived with exposed bone in their mouths. “It looks like a piece of ivory with little tiny holes in it,” said he told Gina Kolata of the New York Times on June 2, 2006.

“The one drug they were all on was bisphosphonates,” he added.

Dr Ruggiero said he tried scraping away the dead bone and letting it heal, but that only made things worse. “We were creating a larger bone wound that didn’t heal,” he said.

He told the Times that he called local cancer specialists, but “they said they did not have any experience with this kind of complication.”

Attorneys say Merck is going to have a hard time trying to defend Fosamax cases by saying something else caused ONJ, as it has in Vioxx cases, because so few things cause the disease.

In a nutshell, the lawsuits against Merck allege that the company aggressively marketed Fosamax as safe, despite knowing about the potential and dangerous ONJ, without warning doctors and prospective patients about it.

In addition, attorneys say, a jury in a Fosamax case may be swayed by viewing first-hand a disfigured plaintiff suffering from ONJ.

Filed under: 2006, Fosamax, Merck, ONJ

FDA needs to Reevaluate Fosamax Safety

Evelyn Pringle November 10, 2006

The FDA is facing mounting accusations that it puts more effort into protecting drug company profits than protecting American consumers from unsafe drugs and Merck’s Fosamax is but the latest example of this unhealthy allegiance.

According to the 2003 report by the Office of Inspector General of the Department of Health and Human Services, a survey of FDA’s own drug reviewers revealed that 66% of the lacked confidence in the FDA’s safety monitoring of marketed drugs, and 18% said that they had felt pressure to approve a drug despite reservations about its quality, efficacy, or safety.

A March 2006 report to Congress on an investigation of the FDA’s ability to monitor drug safety by the Government Accountability Office found that the “FDA lacks clear and effective processes for making decisions about, and providing management oversight of, postmarket safety issues.”

The GAO also said that the FDA’s performance was undermined by infighting between drug evaluation administrators whose allegiance is with industry, and the Office of Drug Safety.

Most recently, five experts who are past and current members of FDA Drug Safety Advisory Panels say the FDA’s safety studies often miss serious problems with drugs, both before and after a drug is approved.

Critics contend that the problem stems from the fact that the FDA does not have the authority to remove drugs from the market, or force a company to change a drug’s warning label, or issue sanctions against drug companies that do not properly monitor their products.

The group of experts, who published a critique of the agency in the Archives of Internal Medicine, includes current panel members Curt Furberg, Robyn Shapiro and Arthur Levin, and former panel members Peter Gross and Brian Strom.

They recommend that Congress take steps to improve the FDA’s monitoring of drug safety to include:

1. Providing the FDA with more legal authority to pursue safety violations;
2. Creating a “conditional” drug approval policy for certain types of drugs;
3. Providing the FDA with additional funding to improve safety-monitoring operations and require that it do so;
4. Mandating a broader representation of safety experts with fewer conflicts of interest on advisory panels; and
5. Banning consumer advertising of newly approved drugs until they have been on the market long enough to detect safety issues.

In addition, the group recommends that a new agency, the Center for Drug Safety, be created outside of the FDA’s Center for Drug Evaluation and Research.

The Institute of Medicine also recently suggested a ban on consumer advertising for newly approved drugs until a drug has been on the market long enough to gauge whether any serious problems are likely to occur.

Many experts say that in recent years the mass marketing of newly approved drugs in many instances has proven to be disastrous.

On October 31, 2006, Ronald Brown, a professor of oral diagnosis at the Howard University College of Dentistry, wrote an editorial in the Washington Post to say that he found it especially troubling to see television ads for bisphosphonates such as Boniva and Fosamax.

“Certainly,” he wrote, “these medications appear to be useful in treating osteoporosis, but they also appear to have serious risks in an as-yet-unknown percentage of patients.”

“Jawbone infections known as bisphosphonate-associated osteonecrosis (BON),” he said, “have serious morbidity and mortality issues and are difficult to treat.”

“It is scandalous to allow these drugs to be advertised on television,” he states.

Merck has spent a fortune on promoting Fosamax and it has paid off well. In fact, for 2005, it was announced that Fosamax was the highest scoring medical journal ad at The Doctors’ Choice awards luncheon on October 19, 2006, in New York City, with a 3-page Fosamax ad from FCB HealthCare in the generalist physician category. The ad appeared in both general practice and OB/GYN medical journals.

The Doctors’ Choice annual study is conducted by the Association of Medical Publications, and researches physicians’ attitudes toward product advertising via a web-based study of 315 ads from the 200 most widely advertised products. More than 6,250 practitioners responded with their preferences in medical advertising messages.

Fosamax was hailed as a miracle drug when it came on the market a decade ago.

However, a study published in the October 2006, Journal of Bone & Mineral Research, Fracture Incidence & Characterization in Patients on Osteoporosis Treatment: The ICARO Study, found that the clinical trials Merck touts as proof that Fosamax is effective, actually overstate the benefits of Fosamax in both the clinical and practical setting.

The study found that unless patients were taking Vitamin D and calcium supplements along with Fosamax, there was a poor bone fracture reduction leading medical experts to wonder whether the positive results in the studies were indeed due to Fosamax or the supplements alone.

The drug has come under fire recently after an Annals of Internal Medicine study linked the use of bisphosphonate drugs to osteonecrosis of the jaw (ONJ), often referred to as dead jaw.

ONJ is an irreversible, disfiguring condition in which bone tissue dies and fails to regenerate and most often becomes known when patients have dental extractions or implants and oral surgery. Symptoms of the condition include excruciating pain, swelling, exposed bone, and loose teeth.

This Fosamax side effect directly contradicts its intended purpose, which is to strengthen bones and prevent bone loss in people with osteoporosis. There also have been reports that Fosamax does indeed increases bone density, but the new bone that develops is too brittle and more prone to fracture.

Although studies have shown that intravenous use of bisphosphonates is more likely to cause ONJ, pill form is also a big concern due to the heavy promotion of Fosamax for life-long treatment, and the high number of prescriptions written each year for younger patients, especially women.

Critics point out that once a patient takes Fosamax for several years, the damage can occur long after a patient stops taking the drug.

According to Dr Mark Steinberg, an oral surgeon at Loyola University Medical Center, “These drugs stay in your body for 10 years, maybe even more.”

“So, just by stopping it, it doesn’t mean it’s going to go away right away,” Dr Steinberg said during an interview CBS News.

According to a study in the November 2006, journal Expert Opinion on Drug Safety, scientists are considering two theories on exactly how the drugs cause of ONJ.

The first is that bisphosphonates cause cell death within the jaw bone and make it more prone to chronic infection. The other theory is that the bone is alive until it is injured and infected and the bisphosponates hinder the formation of fresh bone surface for reestablishment of bone cell coverage due to a reduced resorptive ability.

The study’s author, Professor Per Aspenberg, from Linkoping University in Sweden, notes that the theories are compared based on recent but scarce literature. “None of them can be completely refuted,” he writes, “but the demonstration of living osteocytes within the lesion and the number of necessary assumptions speak against the theory of a primary, bisphosphonate-induced necrosis.”

The American Association of Oral and Maxillofacial Surgeons has said that its members are reporting as many as 5,000 cases of ONJ related to bisphosphonates.

Filed under: 2006, FDA, Fosamax, Merck, ONJ

Behind the Scenes Snake Oil Salesmen

Evelyn Pringle March 7, 2007

While the pharmaceutical industry’s corrupt practice of peddling ineffective drugs and concealing dangerous side effects has come under scrutiny in recent years, critics say the contributions of the research scientists, academics, medical journals, and the FDA deserve far more credit for their part in the industry’s overall marketing schemes.

Drug companies now control clinical trial design, the criteria for patient selection, the analysis of the research, as well as the results that are reported and the side effects that are not. “In short, in controlling what gets published in journals, the industry controls what gets passed off as medical evidence to influence physician prescribing practices,” according to, “Research and Clinical Practice Guidelines: Can We Trust the Evidence in Evidence-Based Medicine?”, by Dr John Abramson, of Harvard, and Dr Barbara Starfeld, a professor at Johns Hopkins, in the Journal of the American Board of Family Practice.

A report by the UK Parliament in 2005, found that 75% of clinical trials published in the major medical journals, including the New England Journal of Medicine, The Lancet, and the Journal of the American Medical Association, were funded by the industry.

“The sources of knowledge that doctors have been trained to trust have been taken over by the medical marketing community,” says Dr Abramson, author of Overdose America. “We can never trust what we’re reading.”

Adding to the problem, when a trumped up study is published, Dr Timothy Scott, author of, “America Fooled,” says few doctors in private practice have a research design background that would enable them to recognize a fraudulent study.

“The blame lies,” he explains, “not so much with individual physicians as with the drug approval system and the drug companies which today are very knowledgeable about how to design a study that is fraudulent yet capable of getting their drug approved and still be used in marketing and advertising.”

“Most academic physicians,” Dr Scott states, “could look at many of the studies used to promote drugs and know very quickly they are worthless, but this is not a skill that many private practice physicians have.”

“Journals have devolved into information laundering operations for the pharmaceutical industry,” says Richard Horton, editor of the Lancet, in the May 17, 2005 PLos Medical Journal.

Doctors may not be as uninfluenced by the drug ads as they would like to believe, he says, but the bigger problem lies with the original studies, particularly the clinical trials, published by journals. Mr Smith notes that doctors consider randomized controlled trials as one of the highest forms of evidence and states:

A large trial published in a major journal has the journal’s stamp of approval (unlike the advertising), will be distributed around the world, and may well receive global media coverage, particularly if promoted simultaneously by press releases from both the journal and the expensive public-relations firm hired by the pharmaceutical company that sponsored the trial.

For a drug company, a favourable trial is worth thousands of pages of advertising, which is why a company will sometimes spend upwards of a million dollars on reprints of the trial for worldwide distribution.

“The doctors receiving the reprints may not read them,” Mr Smith says, “but they will be impressed by the name of the journal from which they come.”

He contends that the quality of the journal “will bless the quality of the drug.”

On December 13, 2005, the Wall Street Journal reported on a 1999 document that surfaced in litigation that described Pfizer’s strategy for publishing articles in medical journals to market the antidepressant, Zoloft.

The document, prepared by a unit of advertising agency WPP Group, included 81 different proposed articles for journals to “promote the drug’s use in conditions from panic disorder to pedophilia,” the WSJ states.

For some, the name of the author was listed as “TBD,” short for “to be determined,” even though the article or a draft was listed as completed. And several of the articles did appear in publications such as the Journal of the American Medical Association, without disclosing the outside writers, the WSJ said.

In 2004 New York State Attorney General, Eliot Spitzer, sued GlaxoSmithKline charging that the company had engaged in “repeated and persistent fraud” in concealing the negative results from a number of studies that showed Paxil increased the risk of suicidality and was ineffective when prescribed to children.

Critics say that even when positive results of studies are reported, the methodology used often leads to questionable results because the research is carried out in a way that ensures that a drug will be found effective, according to Joseph Wyatt and Donna Midkiff of Marshall University, in Biological Psychiatry: A Practice in Search of Science (2006).

Prior to the start of a study, they explain, researchers attempt to remove all subjects who might respond favorably to a placebo before dividing the patients into the drug and the placebo groups for the actual study.

To that end, for up to 3 weeks, all trial subjects are given a placebo and observed in what is referred to as the placebo “run-in” or “wash-out” period and those subjects who improve on a placebo are removed and have no further participation in the study.

The study is then conducted with the remaining subjects divided into the drug and placebo groups and the predictable outcome is that the drug is more effective than placebo. However, according to Biological Psychiatry, even when playing with a stacked deck, the results of studies are frequently negative or only marginally positive.

For example, a review of 38 studies on SSRI antidepressants such as Prozac, Zoloft, Paxil, Serzone, Celexa and Effexor, conducted during 1987-1999, showed an average 10-point improvement in mood for patients who took the drugs, and an 8-point improvement for those who took a placebo (Kirsch, Moore, Scoboria & Nicholls, 2002).

“It is doubtful,” Joseph Wyatt and Donna Midkiff say, “that the two-point average advantage for the drugs is meaningful in the real world in which patients function every day, or that the drugs would have had even that slight advantage over placebo had it not been for the wash-out methodology.”

Psychiatrist, Dr Grace Jackson, author of, “Rethinking Psychiatric Drugs,” and one of the leading US authorities on psychiatric drugs, explains why the study designs used to gain FDA approval for atypicals antipsychotics, like Zyprexa, were seriously flawed.

In typical drug trials, she notes, study participants are required to go off all medications for 2 weeks and at the end of the two weeks, half of the patients are given the new drug and half are given a sugar pill. Then, at the end of 4 weeks, the researchers assess which patients seem to be doing better.

“The problem with these studies is the first two weeks,” Dr Jackson says, “because those patients who had previously received medications may have gone into abrupt withdrawal.”

These studies make a new drug look good, she explains, only because no one is paying attention to the fact that patients in the placebo group may be going through withdrawal.

As an example, Dr Jackson points to a study that compared Haldol and Zyprexa in which researchers took patients off Haldol, and gave some patients Zyprexa and the others a placebo. Naturally, she notes, those on Zyprexa did better than the patients taking a sugar pill and going through withdrawal.

According to Dr Jackson, all the published studies are on Haldol and Zyprexa or Zyprexa and placebo, and in every one of them, “the researchers have ignored the effects of withdrawal symptoms due to the placebo washout period.”

“This is a trick,” she states, “that drug companies used for every single psychiatric drug.”

According to the January 15, 2006, LA Times when it comes to the role of medical journals having a positive impact on the marketing of a drug, “There is no better cautionary tale than the unwarranted success of Vioxx.”

The only reason doctors prescribed Vioxx was because it was heavily promoted as being safer than other anti-inflammatory drugs when in fact Merck’s own study showed that Vioxx caused more heart attacks, blood clots and strokes, even in patients with no prior history of cardiovascular disease, and was no better at pain relief than the drugs already on the market.

The Times pointed out that the FDA and Merck knew all this and said American doctors prescribed $7 billion worth of Vioxx, “Because the New England Journal article that ostensibly reported the results of Merck’s study didn’t even mention either the cardiovascular or the overall dangers of Vioxx.”

“Instead,” the Times said, “it reported only selective data on heart attacks and strokes allowing Merck to claim that Vioxx wasn’t a risk to people without a history of these problems.”

In the not too distant past, the majority of research funding came from the Federal government, through the National Institutes of Health. However, major research institutions, like Harvard Medical School for instance, now receives nearly 25% of its research funding from nonfederal sources, including nearly $3.5 million from Aventis Pharmaceuticals, $2.5 million from Bristol-Myers Squibb, and $2.1 million from Merck.

In addition, on April 12, 2006, The Phoenix, reported that SEC filings show Harvard stock holdings of $16 million worth of Merck, $8 million of Bristol Myers Squibb, $34 million of Johnson & Johnson, and $33 million of Pfizer.

The investments made through research funding pay big dividends. For example, Merck, controlled every aspect of a 2002 study reported in the Annals of Internal Medicine, praising the use of Fosamax for osteoporosis. The paper’s lead author, Susan Greenspan, was a Harvard professor, and the director of the Beth Israel Deaconess Osteoporosis Prevention and Treatment Center.

As it turns out, Merck paid for the recruitment and participation of 327 patients; collected the data from 25 separate facilities, and Merck employees were involved in, “coordinating the early phases of the study,” which translates into controlling the design and execution of the trial, and in “providing expertise in study conduct.”

Most of these details were revealed in the paper’s disclosures but such acknowledgements seldom appear in the media or on internet Web sites where most people learn about studies. Merck also retained full control and ownership of the research itself.

In 2001, the year before Dr Greenspan’s article appeared, Fosamax had a little over $1 billion in sales; in 2003 sales were at $2.7 billion.

Fosamax was promoted extensively and successfully for use by young women on the premise that taking the drug daily early in life would prevent osteoporosis. However, Fosamax has now been linked to jaw bone death, a condition that involves severe pain, infection, loose teeth, exposed bone, loss of function and disfigurement, according to the American Association of Oral and Maxillofacial Surgeons.

Back on July 24, 2006, the Goldsboro News-Argus reported that more than 3,000 published cases of ONJ had been reported since 2003.

On July 11, 2006, the LA Times stated: “As Merck & Co. defends itself against a deluge of litigation involving its pain reliever Vioxx, the pharmaceutical giant also is fielding the first of what could be another wave of lawsuits involving Fosamax, its second-biggest seller.”

In one of the more recent research fiascos, on February 8, 2006, the FDA issued a Public Health Advisory and recommended that doctors limit the use of Trasylol (aprotinin), a drug used to control bleeding in open heart surgery, marketed by Bayer Pharmaceuticals, to patients where the benefit of reduced blood loss outweighed the risks.

The Advisory was based on studies that found Trasylol to be associated with a 48% increase in myocardial infarction, a 109% increase in heart failure, and a 181% increase in strokes, when compared to other drugs, and that patients treated with Trasylol had a risk of kidney failure 259% greater than patients who received no drugs.

On September 21, 2006, an FDA Advisory Committee met to review the findings and when it came time for Bayer’s presentation, Mike Rozycki, Director of US Regulatory Affairs, told the panel that when the company learned of the studies, “We immediately began a comprehensive review of all the data that we had.”

“This was conducted in very close association and under the guidance of the FDA,” he stated. “All that information has been submitted and is under review by the FDA.”

Mr Rozycki specifically said, “Dr. Pamela Cyrus, of Bayer’s U.S. Medical Affairs organization will review the clinical data that Bayer has and that is in the literature for aprotinin.”

At the end of the hearing, the panel decided that there was no need for an additional warning on Trasylol, and Bayer immediately issued a press release stating, “the committee overwhelmingly affirmed (18 yes votes and one abstention) that the totality of clinical data presented in today’s meeting supports acceptable safety and efficacy for Trasylol among coronary artery bypass graft (CABG) surgery patients.”

However, while testifying, Bayer “forgot” to mention the negative results of a study of 67,000 patients commissioned by Bayer in June 2006, from a private research firm that confirmed the risks associated with Trasylol discussed at the hearing, that Bayer had received on September 14, 2006. When the study was not mentioned at the hearing, one of the researchers who worked on it informed the FDA of its existence.

After reviewing the research, the FDA issued a new advisory saying the results of the study demonstrate “that use of Trasylol may increase the chance for death, serious kidney damage, congestive heart failure and strokes.”

One of the latest cases of a drug company concealing a drug’s dangerous adverse events and lack of efficacy, involves the antibiotic, Ketek, made by Sanofi-Aventis.

During the approval process for the drug, FDA reviewers learned that evidence of liver damage was found early in the company’s own clinical trials but it was suppressed. In addition to liver problems, Ketek has been found to cause blurred vision and loss of consciousness.

To support approval, Aventis also submitted fraudulent studies to the FDA with the conduct in one study so extensive that the doctor involved, Anne Kirkland-Campbell, was sentenced to nearly 5 years in prison.

At a Congressional hearing on September 13, 2007, Dr David Ross, the primary reviewer and safety team leader during the Ketek approval process, told the Committee that top FDA officials approved Ketek despite knowing that it could kill people and that tens of millions of people would be exposed to it. Because Ketek was approved, Dr Ross said, “dozens of people have died or suffered needlessly.”

Internal FDA emails that surfaced during Congressional investigations show that at least 3 other safety officials, Dr Charles Cooper, Dr David Graham, and Dr Rosemary Johann-Liang, had also expressed serious concerns about Ketek.

“I tried to argue that given Aventis’s track record in which they have proven themselves to be nontrustworthy that we have to consider the possibility that they are intentionally doing a poor job of collecting the postmarketing data to protect their drug sales,” Dr Cooper said in an email.

A former employee of Pharmaceutical Product Development (PPD), the contract research organization hired by the Aventis for the Ketek studies, also testified at the hearing and said both Aventis and the PPD were aware of fraudulent data in the clinical trials.

Ann Marie Cisneros was a clinical research associate for PPD who monitored Dr Kirkman-Campbell’s site and said, “Dr Kirkman-Campbell indeed had engaged in fraud.”

“But what the court that sentenced her did not know,” she said, “is that Aventis was not a victim of this fraud.”

“On the contrary,” she testified, “I knew it, PPD knew it, and Aventis knew it.”

Mr Cisneros told the panel that a number of “red flags” at the trial site were apparent. For example, she said, over 400 patients were enrolled at $400 per patient for Ms Kirkman, and by comparison, another site in Gadsden had enrolled just 12 patients.

In addition, she noted, no patients had withdrawn from the study and none were lost to follow up, “an unusual occurrence given the number of subjects,” she said.

Sanofi-Aventis, for its part, submitted a typical fraudulent statement for the hearing saying in part: “It was only after FDA criminal investigators conducted an evaluation having tools at their disposal that may not be available to study sponsors, that the fraud was discovered.”

Senator, Chuck Grassley (R-Iowa), also gave a statement and described the on-going attempts to frustrate his investigation into why FDA officials approved Ketek and said:

The FDA and the Department of Health and Human Services have put up so much resistance to my efforts to find out what happened inside the FDA with a relatively new antibiotic called Ketek that I can only wonder what there is to cover up.

Every excuse under the sun has been used to create roadblocks, he said, even in the face of Congressional subpoenas requesting information and access to FDA employees.

Immediately before the hearing, the FDA announced the removal of approval for 2 of the three uses for Ketek. The drug is now approved only to treat mild to moderate severity of community acquired pneumonia, acquired outside of hospitals or long-term care facilities.

Filed under: 2007, antipsychotics, Fosamax, Ketek, SSRIs, studies, Trasylol, Vioxx

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