Hospital error blamed for more infant overdoses

CORPUS CHRISTI, Texas (AP) – The case of 14 babies who received accidental overdoses while in intensive care has raised new questions about how a common blood-thinning medication could be given to infants repeatedly in the wrong dosage.

Unlike a previous case involving twins of actor Dennis Quaid, the Texas newborns got the overdose because of an error at the hospital pharmacy, not a labeling problem.

Quaid sued one of heparin’s manufacturers last year after his children’s overdose was traced to a hospital pharmacy worker who grabbed vials of the wrong dosage because the labels looked almost identical if turned a certain way.

In Corpus Christi, pharmacy workers at Christus Spohn Hospital South made what the hospital called a “mixing error.” The two workers went on voluntary leave.

The heparin, which was 100 times stronger than recommended, was given to 14 infants in the hospital’s neonatal intensive care unit on July 4.

Two of the babies involved—twins who were born one month premature—have died, although the hospital said its physicians have found no direct links to the overdose. Autopsies are being performed.
In addition to the 14 infants, three other babies who were discharged shortly after the overdoses may also have received too much heparin, but they showed no ill effects.

Nurses discovered the error Sunday and immediately gave the hospitalized infants a drug to counteract the effects.

At a news conference Friday, the grandmother of the children who died said the family was devastated as it prepared to hold funerals for the babies on Saturday, the same day relatives had planned a baby shower for their mother.

“We want answers,” Maggie Chapa said. “We want to know what happened.”
A patient safety expert said hospitals are often slow to change.

“It is frustrating to people that we have had other heparin issues,” said Diane Pinakiewicz, president of the National Patient Safety Foundation.

“When you have complex systems interfacing with humans, we’re never going to have perfection,” she added. But “our job is to get as close to perfection at all times.”

Hospitals around the nation have made changes to the way they handle heparin, which is one of the most common additives to intravenous solutions.

For example, at Texas Children’s Hospital in Houston, vials of heparin are no longer available in the neonatal intensive care unit. Nurses must get it directly from the pharmacy. That would not have helped in the Corpus Christi case, where the error was made in the pharmacy, but it may have avoided a situation like the one that threatened Quaid’s twins in Los Angeles.

“You always have to go on the premise that somebody is going to make a mistake,” said Dr. Eric Eichenwald, medical director of the unit. “So you have to make it really, really hard to make a mistake.”

In 2006, Methodist Hospital in Indianapolis gave six babies doses 1,000 times stronger than recommended. Vials of the wrong dosage of the drug had been placed in a medicine cabinet in the neonatal intensive care unit, and nurses didn’t catch the mistake before the babies were given the medication. Three of those infants died.

Pharmacy technicians normally placed premeasured vials of a less concentrated form of heparin in a computerized drug cabinet. Nurses then had to enter their personal code and the specific patient’s code to open the cabinet. When the drawer opened to display an assortment of drugs, the nurse would select the correct one and then enter the amount withdrawn.

But the pharmacy technician mistakenly placed in the cabinet a more concentrated form of heparin.
The following year, at Cedars-Sinai Medical Center in Los Angeles, two pharmacy technicians failed to verify the correct concentration of the heparin they placed in the pediatrics ward. Quaid’s twins, as well as another infant, received doses similar in strength to those given in Indianapolis. The nurses who administered the drug also failed to check the dosage. All three children recovered.

Quaid sued Baxter Healthcare Corp. for negligence, arguing that the two concentrations of the drug looked almost identical. The company had already changed its packaging to add a red caution label that had to be torn off before opening.

Cedars-Sinai instituted additional training and required that four pharmacy technicians verify such “high-alert” medications before putting them in any hospital units.

Earlier this year, the U.S. Food and Drug Administration also investigated hundreds of cases of adverse reactions to injections of heparin made by Baxter International. The reactions were blamed on a tainted supply originating in China.

The tainted heparin was not involved in the Texas case, Baxter said.

Don’t you just love Diane’s statement: “When you have complex systems interfacing with humans, we’re never going to have perfection.”

Pfizer Warns of Inhaled Insulin Lung Cancer Risk

NEW YORK (Reuters) – Pfizer Inc and Nektar Therapeutics said on Wednesday clinical trials of the inhaled insulin Exubera found increased cases of lung cancer, leading Nektar to stop seeking a marketing partner for the troubled product and abandon it.

Nektar shares tumbled 25 percent, while shares of MannKind Corp, which has been developing its own inhaled insulin, plummeted 58 percent. Pfizer was down slightly at $20.90.

The lung-cancer revelation dealt a final setback to Exubera, which held the promise of letting diabetics avoid needle sticks and was once projected by Pfizer to be a $2 billion-a-year blockbuster. Instead, Exubera has been a commercial flop that has sullied the inhaled insulin field.

Over the course of the clinical trials, Pfizer said six of the 4,740 Exubera-treated patients versus one of the 4,292 patients not treated with Exubera developed lung cancer. One lung cancer case was also found after Exubera reached the market.

Pfizer said on Wednesday it updated the product’s labeling to include a warning with safety information about lung cancer cases found in patients who used Exubera, which U.S. regulators approved in January 2006.

The warning states all patients who developed lung cancer had a history of cigarette smoking, and that too few cases existed to determine whether the development of lung cancer is related to Exubera use.

HIGH HOPES

Despite high hopes for Exubera, it garnered few prescriptions. The medicine was dogged by concerns about lung safety and about the inconvenience of the bulky device used to administer the product.

Pfizer said in October it would stop marketing Exubera and returned rights to Nektar. Pfizer reported $12 million in Exubera sales through the first three quarters of 2007; in October it took a pretax charge of $2.8 billion related to exiting Exubera.

Since then, Exubera has not been actively marketed but existing patients were able to get prescriptions while transitioning to an alternative therapy.

The warning in the label stemmed from an ongoing review of data from the Exubera clinical trial program and post-marketing experience by Pfizer and the U.S. Food and Drug Administration, Pfizer said.

Pfizer said it will be discussing withdrawals of marketing authorizations for Exubera with regulatory agencies.

Nektar said it will cease all spending associated with its inhaled insulin programs, including a next-generation version in early clinical testing, and will not incur charges related to the event.

“The news of an increased number of lung cancer cases is disappointing given that as recent as the year-end quarterly conference call, management reiterated the high level of interest from potential partners,” Pacific Growth Equities analyst Patricia Bank said in a research note.

MOVED AWAY

Bank downgraded her rating on Nektar stock to “Neutral” from “Buy” on the news.

Nektar Chief Executive Howard Robin said in a statement the company has moved away from inhaled insulin the past year. Its experimental pipeline includes a treatment for pneumonia in the lung about to enter late-stage development, and mid-stage projects for colorectal cancer and opioid-induced constipation.

Since Pfizer’s exit last year, Eli Lilly <LLY.N> and Novo Nordisk <NOVOb.CO> also ended inhaled insulin development programs.

MannKind has been steadfast in its commitment to its experimental inhaled insulin, Technosphere Insulin, saying it held advantages over the other products.

But Natixis Bleichroeder analyst Jon LeCroy downgraded his rating on MannKind stock to “Sell” from “Hold” on the Exubera news.

“We view this as an absolute disaster for MannKind and do not see a believable scenario in which the FDA would approve another inhaled insulin,” LeCroy said in his downgrade note.

MannKind shares were off $3.39 at $2.46 in morning trading on the Nasdaq to a multiyear low. Nektar shares fell $1.79 to $5.40.

If this was a regular company, say, ummm, like Wal-Mart, how fast do you think they’d be out of business? Oh, that’s right, the left is trying to destroy Wal-Mart. Sorry, bad example.

FDA Raises Estimate of Deaths Linked to Blood Thinner

FDA(WP) – The Food and Drug Administration yesterday raised from 19 to 62 its estimate of the number of people who may have died after having allergic reactions to contaminated Chinese-produced batches of the blood thinner heparin.

The new statistics on fatalities, which the FDA had promised for weeks, were posted on the agency’s Web site.

The posting said that the reports of allergic reactions or low blood pressure after the administration of heparin do not mean the drug was the cause of death “in all cases.” But the agency provided comparison statistics showing that in 2006, three people were reported to have died following allergic reactions to heparin.

In addition, FDA’s month-by-month count of adverse-event reports involving heparin showed that 47 of the 62 deaths associated with allergic reactions occurred from November through February.

The FDA said it had received reports of 103 people who died after receiving heparin last year, 62 of whom experienced an allergic reaction or a plunge in blood pressure. The others showed no signs of allergic reaction.

Erin Gardiner, spokeswoman for Baxter International, which distributed the contaminated heparin, said last night that the company had received reports of 38 deaths associated with the drug, but its officials maintain that four of those were the result of unexplained allergic reactions. The rest of the reported deaths, Gardiner said, were not associated with Baxter’s heparin, were probably caused by other illnesses or conditions, or were based on information too cursory to be proved one way or the other.

The increase in reports of suspected heparin fatalities does not mean that people are still being harmed by the drug. The contaminated Baxter heparin was taken off the market several months ago, but earlier cases are still being reported and investigated.

Heparin, which is made from a compound found in pig intestines, has been widely used for decades during surgery and kidney dialysis.

FDA officials have said that some Chinese-produced heparin and active ingredients used to make it were contaminated with a substance that chemically resembles heparin but was different enough to have caused the sudden spike in allergic reactions.

In previous statements, the agency said it did not know whether the cheaper contaminant — which may have come from pig cartilage — was deliberately added to the crude heparin or was the result of a production problem.

China is now the world’s largest producer of the raw ingredients in heparin. The contaminated batches of the drug have increased concerns among lawmakers and the public about the globalization of drug-manufacturing in lightly regulated nations. In response to criticism that it was not properly overseeing Chinese companies that make drugs for American patients, the FDA recently announced that it would soon open its first office there.

It took sophisticated, never-before-used tests to detect the contaminated heparin, and identifying the contaminant as a form of chondroitin sulfate took additional weeks of laboratory work.

Let’s boycotts all imports from fucking CHINA! So what if we have to pay more – maybe we can reduce our unemployment stats – ever think that that would help this country, stimulate the economy and keep the government from taxing us to death.

Drug Makers Near Old Goal: A Legal Shield

For years, Johnson & Johnson obscured evidence that its popular Ortho Evra birth control patch delivered much more estrogen than standard birth control pills, potentially increasing the risk of blood clots and strokes, according to internal company documents.

But because the Food and Drug Administration approved the patch, the company is arguing in court that it cannot be sued by women who claim that they were injured by the product — even though its old label inaccurately described the amount of estrogen it released.

This legal argument is called pre-emption. After decades of being dismissed by courts, the tactic now appears to be on the verge of success, lawyers for plaintiffs and drug companies say.

The Bush administration has argued strongly in favor of the doctrine, which holds that the F.D.A. is the only agency with enough expertise to regulate drug makers and that its decisions should not be second-guessed by courts. The Supreme Court is to rule on a case next term that could make pre-emption a legal standard for drug cases. The court already ruled in February that many suits against the makers of medical devices like pacemakers are pre-empted.

More than 3,000 women and their families have sued Johnson & Johnson, asserting that users of the Ortho Evra patch suffered heart attacks, strokes and, in 40 cases, death. From 2002 to 2006, the food and drug agency received reports of at least 50 deaths associated with the drug.

Documents and e-mail messages from Johnson & Johnson, made public as part of the lawsuits against the company, show that even before the drug agency approved the product in 2001, the company’s own researchers found that the patch delivered far more estrogen each day than low-dose pills. When it reported the results publicly, the company reduced the numbers by 40 percent.

The F.D.A. did not warn the public of the potential risks until November 2005 — six years after the company’s own study showed the high estrogen releases. At that point, the product’s label was changed, and prescriptions fell 80 percent, to 187,000 by last February from 900,000 in March 2004.

Gloria Vanderham, a Johnson & Johnson spokeswoman, said the company acted responsibly.

“We have regularly disclosed data to the F.D.A., the medical community and the public in a timely manner,” Ms. Vanderham said. “Ortho Evra is a safe and effective birth control option for women when used according to the labeling.”

But Janet Abaray, a plaintiff’s lawyer from Cincinnati, said that Johnson & Johnson took advantage of an agency overwhelmed by its many responsibilities.

“Johnson & Johnson knew that F.D.A. does not have the funding or the manpower to police drug companies,” Ms. Abaray said.

A series of independent assessments have concluded that the agency is poorly organized, scientifically deficient and short of money. In February, its commissioner, Andrew C. von Eschenbach, acknowledged that the agency faces a crisis and may not be “adequate to regulate the food and drugs of the 21st century.”

The F.D.A. does not test experimental medicines but relies on drug makers to report the results of their own tests completely and honestly. Even when companies fail to follow agency rules, officials rarely seek to penalize them. “These are scientists, not cops,” said David Vladeck, a professor at Georgetown Law School.

Last month, at a trial over the schizophrenia drug Zyprexa, Dr. John Gueriguian, a scientist who worked at the F.D.A. for two decades, testified that the agency did not always ask for strong warnings even if it believed a drug was risky. Companies typically oppose warnings, and the agency knows it must compromise on its requests or face years of delay, Dr. Gueriguian said.

“We at the F.D.A. know what we can obtain and we cannot obtain,” Dr. Gueriguian said. “We have many, many problems, and we have a management system — what we can’t obtain we will not ask.”

For years, top officials at the agency acknowledged that lawsuits could aid the agency’s oversight of safety issues. In the last decade, suits over Zyprexa, the withdrawn pain pill Vioxx, the withdrawn diabetes medicine Rezulin, the withdrawn heartburn medicine Propulsid and several antidepressants have shown that companies played down the risks of their medicines and failed to disclose clinical trials to the public even as they have aggressively marketed their drugs.

But now, the agency says a proliferation of lawsuits could lead to an overlapping patchwork of rules that would burden companies and might discourage patients from taking useful medicines.

The Ortho case, however, suggests that Johnson & Johnson, like other drug makers, is not always quick to tell the F.D.A. about potential problems with its medicines.

In 1996, the company told the agency it planned to develop the Ortho Evra patch in part because it would be likely to expose women to less estrogen than pills. The company suggested that the body would not break down hormones delivered via the patch as readily as the pill, so lower doses could be used to achieve contraception. And unlike the pill, which must be taken daily, the patch is changed weekly.

High doses of estrogen are known to raise the risk for blood clots that can cause heart attacks and strokes.

But a crucial trial completed in 1999 showed that the patch delivered 30 to 38 micrograms of estrogen into the bloodstream each day, according to company documents.

Because up to half of the estrogen in pills is lost in the digestive tract before it reaches the blood, the study suggested that the patch delivered an amount of estrogen that could be as high as a pill containing 76 micrograms of estrogen. In 1988, the F.D.A. banned birth control pills with more than 50 micrograms of estrogen.

But the study’s author, Dr. Larry Abrams, who has since retired from Johnson & Johnson, decided to apply a “correction factor” to the results of the 1999 trial, according to documents. He claimed that the patch actually delivered about 40 percent less estrogen than the trial results showed — about 20 micrograms a day.

Dr. Abrams made the change, according to his deposition, to adjust for the different ways the body metabolizes hormones from pills and patches. This adjustment was never part of the study protocol, a plan filed with the F.D.A..

“The judgment was made by the pharmacokeneticists at the time that in doing the calculation, it was probably appropriate to make that correction,” Bob Tucker, a lawyer representing Johnson & Johnson, said in an interview Thursday. “Later on when people looked at it in a different time frame, they concluded that probably the correction shouldn’t be applied.” The company mentioned its decision to use the “correction factor” only once in a 435-page report filed with the F.D.A., and then only in a complex mathematical formula. When the study was published in 2002, there was no reference to the alteration.

Mr. Tucker said that the F.D.A. was aware of the “correction factor.”

Clinical trials conducted before the patch was approved raised other red flags, as patients complained of breast soreness and nausea. “The side effects seem related” to high estrogen doses, one company scientist wrote in an e-mail message.

Two other studies, one conducted in 1999 and another in 2003, confirmed that the patch released more estrogen than the pill. Still, Johnson & Johnson delayed reporting those results to the food and drug agency, according to documents that have been made public in lawsuits.

After the patch was approved, the company marketed it as releasing 20 micrograms of estrogen to the blood every 24 hours, a figure it now acknowledges was inaccurate. It also acknowledges that the patch releases more estrogen than the pill but says that the estrogen released under the two methods cannot be directly compared.

The New York Times provided the drug agency with a copy of a court brief and asked whether agency medical reviewers were aware of the “correction factor.”

Rita Chappelle, an F.D.A. spokeswoman, replied, “At present, we are reviewing the allegations and cannot comment further at this time.”

Prescriptions for the patch grew rapidly after its introduction, reaching more than 900,000 by March 2004, according to data from Wolters Kluwer, a company that tracks prescription trends. But as the use of the patch rose, so did reports of side effects.

By 2004, after the death of Zakiya Kennedy, an 18-year-old college freshman in New York, food and drug officials had become concerned.

In November 2005, the agency announced that it had placed a warning that the patch “exposes women to higher levels of estrogen than most birth control pills.”

Since then, an epidemiological study has shown that women on the patch can have as much as double the risk of blood clots than those taking pills. And prescriptions for the patch have fallen 80 percent.

Still, lawyers for Johnson & Johnson say that patients should not be allowed to sue the company because the F.D.A. approved the patch and its label.

“F.D.A. is responsible for making those decisions,” said John Winter, a lawyer for the company.

Judge David A. Katz of Federal District Court for the Northern District of Ohio is expected to rule soon on whether any of the lawsuits against Johnson & Johnson can go forward.

In the fall, the Supreme Court will hear a separate pre-emption case involving Wyeth, another drug company. Chris Seeger, a plaintiffs’ lawyer who has about 125 Ortho Evra cases, said he expected the court to rule in Wyeth’s favor.

“Our lawsuits are the ultimate check against the mistake made by the government, or fraud made by the companies against the government, or just an underfunded bureaucracy stretched thin,” he said.

I’m too angry to make any sense of this.