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On April 29, 2008, a Congressional subcommittee heard from family members whose loved ones suffered deaths as a result of contaminated Heparin. The widow of a man who died after receiving contaminated Heparin told the committee “we have a false sense of security” in a land where people expect to be protected and safe. Brushing away tears, Johanna Marie Staples of Toledo, Ohio, said her husband, Dennis, was looking forward to his 60th birthday party on the last day of his life.

Contaminated Heparin, a blood thinner used in dialysis and other treatments, has been connected to 81 deaths and 785 severe allergic reactions, said Rep. Bart Stupak, D-Mich., chairman of the House Energy and Commerce subcommittee on oversight and investigations.

Heparin, made from ingredients imported from China, has been recalled by Baxter International and the FDA blocked imports from the Chinese company. The FDA found the drug was contaminated with oversulfated chondroitin sulfate, which mimics Heparin and thus was not detected in routine testing, Stupak noted.

When and how it was introduced into the product has not yet been determined.

“FDA’s working hypothesis is that this was intentional contamination, but this is not yet proven,” Dr. Janet Woodcock, director of the FDA’s Center for Drug Evaluation and Research, told the panel in her prepared testimony.

Staples told the subcommittee that her husband was looking forward to an evening birthday party at a steakhouse with friends after receiving his dialysis treatment.

But during the treatment he become unresponsive, stopped breathing and went into cardiac arrest, she said. Paramedics rushed him to a nearby hospital but he never regained consciousness, she said.

Colleen Hubley, a dialysis nurses whose husband, Randy, died after receiving heparin, told of a desperate struggle to save his life with cardiopulmonary resuscitation.

“We were certain that no matter what came our way we could handle it together,” she said. “Despite our hope, this man died while I did CPR on him, powerless to save him.”

When her husband came home from a dialysis treatment he suffered diarrhea, abdominal pain and had problems breathing, she said.

At 2 a.m., she said, she awoke to him clutching his abdomen and grabbing his chest, unable to breathe. She did CPR and called paramedics who struggled to get a breathing tube in his throat because of swelling.

“I watched my husband and my best friend slip away before my eyes,” she said. “I never thought the lifesaving medication we were relying on could be contaminated.”

Randy Hubley’s death came just a month after that of his mother, Bonnie, under the same circumstances.

Leroy Hubley, dabbing his eyes with a handkerchief, told of losing both wife and son, adding: “I want to know if my daughter, Dawn, and millions of others who continue to receive dialysis are safe.”

He told, too, of Bonnie suffering diarrhea, pain and trouble breathing and being rushed to a hospital where doctors recommended removal of her breathing tube to end her suffering.

“Christmas music played in the background as each one of us said our goodbyes,” said a shaking Leroy Hubley. “And the nightmare returned only weeks later when my son, Randy, started dialysis at the same clinic.”

The Hubleys also reside in the Toledo area.

The FDA’s Woodcock told the subcommittee that in recent years major changes have occurred in where drugs are made.

For example, in 2007 the agency received only about 150 applications for approval to make generic drugs in the United States compared to nearly 500 from China and more than 400 from India, she said.

“Great vigilance is required to maintain” drug safety, she said.

Chinese officials have argued that the contaminant could not be the root cause of the allergic reactions and suggested that problem may have occurred in the United States.

Baxter president Robert L. Parkinson Jr., said in testimony prepared for the subcommittee that his company is “greatly concerned that our Heparin product appears to be the target of a deliberate adulteration scheme.”

“The complexity of the global drug supply chain creates new and emerging risks that call for new ways of thinking about, identifying and addressing vulnerabilities, and that resting on old standards even ones that have worked for decades is no longer enough,” Parkinson said.

David Strunce, president of Scientific Protein Laboratories, said in testimony that worldwide problem with contaminated Heparin cannot be traced to how Heparin was processed at the Changzhou SPL factory in China which supplied the material to Baxter. His company holds a majority interest in Changzhou SPL.

Rather, Strunce said, there appears to be deliberate and widespread contamination of the crude Heparin supply in China affecting many manufacturers.

New information has been released linking both Avandia and Fosamax, to adverse events. One study found that long-term use of Avandia increases risk for bone fractures. Additionally, a second study illustrates that Fosamax, which is used to prevent fractures in women with osteoporosis, may be associated with a higher risk of atrial fibrillation, a type of abnormal heart rhythm. Both studies were published in the April 28, 2008 issue of the Archives of Internal Medicine.

An estimated 3.5 million or more U.S. patients take Avandia, experts say. But in 2007, Avandia and four other drugs from the same class were given a “black box” warning, cautioning users of increased heart problems.

The recent study, led by Dr. Christian Meier of University Hospital Basel, Switzerland, looked at links between thiazolidinediones and fracture. It was designed to ascertain whether only women were affected and where fractures were most likely to occur. The research involved 1,020 men and women aged 30 to 89 who had sustained a fracture while taking Avandia, Actos, insulin or another anti-diabetic drug.

Compared to controls, individuals taking Avandia or Actos had more than double the risk of fractures, with the risk with Actos being slightly higher than with Avandia. Drug-associated fractures were particularly common at the wrist and hip. Both men and women were at risk, and the odds for fracture tended to rise with dose of drug taken.

The odds of sustaining a fracture were heightened in patients taking Avandia or Actos for 12 to 18 months and highest in those who were on the medication for two or more years.

Other anti-diabetic drugs did not show the same effect, but thiazolidinediones have a different mechanism of action (working at the cellular level) than other drugs for type 2 diabetes.

The findings echo some previous research that found an increased risk of fractures in women.

For now, the decision to use these particular diabetes drugs should be made on a case-by-case basis, experts said. Women who are postmenopausal and therefore at risk for fractures may want to be more careful, or take other measures to protect their bone health, they said.

“I think the benefit is more than the risk at this point. The benefit is huge in terms of glycemic control,” said Dr. Spyros G.E. Mezitis, endocrinology consultant and clinical investigator at Lenox Hill Hospital in New York City.

“It remains to be seen if the way we practice medicine is going to change. These are important analyses, but we need further evidence,” Mezitis added.

Nancy Pekarek, a spokeswoman for GlaxoSmithKline, the manufacturer of Avandia, noted, “We do have fractures on our label and, in fact, when we saw data from the ADOPT (a previous, long-term trial), we issued a ‘dear doctor’ letter.”

“The fractures have been observed, and we have made physicians aware of that so they can be watching for their patients and choose which drug is appropriate,” Pekarek said. Unlike this trial, the fractures seen in ADOPT were more likely to be in the upper arm, hand or foot as opposed to hip and spine.

The Fosamax study, led by Dr. Susan Heckbert of the University of Washington and Group Health, Seattle, looked at 719 women with confirmed atrial fibrillation in a “real world” setting, versus 966 controls (without atrial fibrillation).

The study found that 6.5% of women who had used Fosamax had atrial fibrillation compared to 4.1% of controls. Based on these findings, the researchers estimated that 3% of new cases of atrial fibrillation in this group of women might be attributable to the use of Fosamax.

Again, the authors cautioned, risks and benefits should be carefully weighed when prescribing the drug.

Other studies have also reported atrial fibrillation as a side effect of bisphosphonates, the class of drugs that includes Fosamax.

Ronald Rogers, a spokesman for Fosamax manufacturer Merck & Co. Inc., called the Fosamax fibrillation association an “old issue.” He also pointed to an article published earlier this year in the British Medical Journal that found no such association.

Rogers also pointed out that the current study is an observational one and therefore subject to limitations not seen in a previous randomized trial. That trial saw an increase in the incidence of “serious” atrial fibrillation among Fosamax patients, he said, but it did not reach a statistically significant difference.

On April 23, 2008, researchers announced they had identified a chemical contaminating the blood-thinner Heparin from China; which confirmed previous FDA findings that it was oversulfated chondroitin sulfate. The investigators said they had used a standard analytical method to find the contamination, which had been difficult to pinpoint before, and said it might be used to screen other batches.

The tainted Heparin killed at least 81 patients and forced a widespread recall of the commonly used blood-thinner. It also caused a diplomatic squabble between U.S. and Chinese officials. “Given the nature of this contaminant, traditional screening tests cannot differentiate between affected and unaffected lots,” Ram Sasisekharan of the Massachusetts Institute of Technology and colleagues wrote in the journal Nature Biotechnology.

“Our analysis suggests effective screening methods that can be used to determine whether or not Heparin lots contain the contaminant reported here.”

Many patients in the United States and Europe who got the contaminated Heparin suffered immediate allergic reactions, with plummeting blood pressure, swelling of the larynx and other severe symptoms.

The researchers freeze-dried the Heparin and used a combination of nuclear magnetic resonance imaging and liquid chromatography-mass spectrometry to analyze its structure.

In addition to a known impurity of Heparin called dermatan sulfate, they found that contaminated lots contain a molecule that looks similar to Heparin and showed it was almost certainly oversulfated chondroitin sulfate.

Oversulfated chondroitin sulfate is derived from a popular supplement used to treat arthritis, among other things. It can resemble Heparin’s active ingredient but is much cheaper, leading some experts to suspect it was added deliberately.

“This study also provides a set of screening methods that could be used to monitor the Heparin supply and ensure the absence of oversulfated chondroitin sulfate contamination,” they wrote.

In February 2008, Baxter International Inc. recalled most of its Heparin products, made with ingredients from China.  Chinese officials said on April 21, 2008 they had tested batches of Heparin used by patients who reported health problems and only some of these batches contained the contaminant.

They said other contaminants; problems with the device used to inject the drug or health factors with the patients who used the drug could be to blame.

Heparin is made from pig intestines that are often collected from small, mostly unregulated farms in China. Baxter maintains the contamination occurred before the product reached Baxter or its raw ingredient supplier.

Democrats in the U.S. House of Representatives have accused the FDA of lax oversight in the case.