Stem Cells’ Electric Abilities Might Help Their Safe Clinical Use
		October 20, 2005 -- Researchers from Johns Hopkins have discovered the presence of functional ion channels in human embryonic stem cells (ESCs). Full Details

Healthorbit.ca

By Rob Stein and Marc Kaufman

A diabetes medicine poised to win Food and Drug Administration approval sharply increases the risk of heart problems, strokes and death, researchers reported yesterday in an analysis that raises new questions about how the agency handles drug safety concerns.

The drug, Pargluva, the first in what had been considered a promising new class of drugs for millions of diabetics, more than doubles the risk of life-threatening cardiovascular complications, the researchers concluded after analyzing the same studies the drug's maker presented to the FDA. They said the agency should not approve the drug until additional research is conducted.

"I do not think it's wise to approve the drug or see the drug marketed until there's a dedicated cardiovascular safety trial," said Steven E. Nissen of the Cleveland Clinic Foundation, who led the analysis. "We have to put safety first."

The FDA notified Bristol-Myers Squibb on Tuesday that the drug was "approvable" pending additional information about the safety issue, but it did not specifically request a new study to examine the risk of cardiovascular problems.

The critique comes as the FDA is struggling to restore its credibility after a series of embarrassing revelations and controversies, including the withdrawal of the blockbuster painkiller Vioxx last year because of serious side effects, a protracted battle over the Plan B morning-after contraceptive, and the abrupt resignation of Commissioner Lester M. Crawford, which remains shrouded in mystery.

The latest controversy underscores the heightened concern over drug safety, with the scrutiny this time on an earlier stage in the FDA approval process. But to some, it also reflects a continuing FDA reluctance to fully embrace drug safety as a paramount concern.

"I think this shows again a system failure at the FDA, that the agency still doesn't give safety the full attention it needs," said Curt Furberg, a drug safety specialist from Wake Forest University and until recently a member of the FDA advisory panel on drug safety.

The reviewers and experts on the advisory panels "don't necessarily have a good understanding of safety," he said.

In a statement yesterday, the FDA said it was taking steps to better identify cardiac problems that might be caused by drugs. "While we cannot specifically discuss this particular drug, the FDA has made significant investments of resources and expertise in developing fundamentally better methods for identifying and monitoring cardiovascular safety issues with all drugs," the statement said.

Pargluva, also known as muraglitazar, is the first of a new class of drugs known as dual-action PPARs. Several similar drugs are already on the market for the nation's 16 million people with Type 2 diabetes, the most common form. The drugs lower levels of blood fats known as triglycerides, raise levels of "good cholesterol" and increase the effectiveness of insulin. Pargluva was designed to combine those effects in a single pill.

As part of its standard drug-review process, the FDA convened a panel of experts on Sept. 9 to examine Pargluva. The committee voted 8 to 1 to recommend approval.

Nissen and two colleagues, alarmed that the only heart specialist on the FDA panel had recused himself because of a conflict of interest, independently reviewed the data from five studies involving 2,374 patients that Bristol-Myers Squibb had submitted. The analysis found those taking the drug had more than twice the risk of death, heart attacks and strokes, and nearly triple the risk when all types of heart problems were included.

The Journal of the American Medical Association released the study yesterday, five weeks ahead of its Nov. 23 publication, because of its public health implications.

While the number of patients in the analysis was relatively small, the trends were so consistent that it would be surprising if the higher risk was because of chance, Nissen said, especially as patients in the studies tended to be healthier than the typical diabetic.

Catherine DeAngelis, the journal's editor, agreed with Nissen's call for more research on the drug's safety. "I'm somewhat perplexed that individuals who are supposed to be looking after the safety of the public would not have asked for the definitive tests before they approve this drug," DeAngelis said.

In a statement, Bristol-Myers Squibb said it is "eager to begin discussions with the FDA to address more fully the cardiovascular safety profile of the compound and to determine what additional information may be necessary." The firm will provide additional safety data to the FDA from ongoing studies and confer with the agency about whether additional studies are needed, a spokesman said.

Nissen, who until recently was chairman of the FDA's Cardiovascular and Renal Drugs Advisory Committee, criticized the FDA advisory panel that reviewed Pargluva for failing to scrutinize the drug more carefully.

"I think this particular FDA advisory panel completely missed the point and did not probe deeply enough," he said. "The company, as expected, presented the data in a way that was favorable to the drug. The FDA did identify these adverse trends but left it to the committee to decide their importance. The panel members did not probe to get beneath the surface. They did not connect the dots."

At the Sept. 9 hearing, David Orloff, the director of the FDA's Division of Metabolic and Endocrine Drugs, set the tone by saying the evidence that the drug may pose a risk was "based on very small numbers of events in individual studies and on small numbers overall."

Bristol-Myers Squibb's Rene Belder told the panel the company had collected safety data equal to 500 patient-years, and that "the results show that the incidence in cardiovascular events, when corrected for duration of exposure, is similar for [Pargluva] and placebo."

But Peter Lurie of Public Citizen's Health Research Group, a consumer group, advised against approval, citing safety concerns. Referring to the FDA's experience with Rezulin, a similar drug that was withdrawn in 2000 because it caused liver problems, Lurie said the "wisest course is to pay attention to the clinical data."

In the end, only Dean Follmann, head of biostatistics at the National Institute of Allergy and Infectious Diseases, voted against recommending approval, saying that because Pargluva is in a new class of drugs, it needed further study before being marketed to millions of people.

The single-action PPAR drugs on the market, Avandia and Actos, have been sold long enough to alleviate concerns they may pose similar risks, Nissen said.

washingtonpost.com

By David Brown

What fallout shelters were to worries about the Bomb, and duct tape and plastic sheeting were to fears of terrorism after Sept. 11, Tamiflu is starting to be for the specter of pandemic influenza.

Across the country, people appear to be building home stockpiles of the prescription antiviral medicine, according to reports by drugstores, pharmaceutical benefit managers and physicians.

The run on Tamiflu was apparently spurred by government warnings, here and abroad, that chances for a worldwide flu epidemic are rising, and by news that Southeast Asia's H5N1 bird flu -- the leading candidate for a pandemic -- is moving westward.

For more than a year, demand for the drug, known generically as oseltamivir, has been rising as more than three dozen countries began to lay in millions of doses for national stockpiles. Retail demand, however, took a sharp upturn last month. A five-day course of two pills a day costs $80 to $90.

The trend worries many physicians and public health experts because widespread home stockpiling could undermine international efforts to fight a flu pandemic. Some doctors are refusing their patients' requests except in special circumstances.

"I do know that I personally can't give everybody who wants Tamiflu a prescription for it. It just doesn't seem right to me," said Harry Oken, 51, an internist in Columbia. "If there really was an avian flu epidemic, people who don't need it have it, and people who really need it can't get it."

Oken said he and his four partners at Charter Internal Medicine are each getting one or two calls a week from patients seeking the medicine. They have agreed not to prescribe it for home stockpiles.

"Last week a patient of mine called about having Tamiflu on hand, and I must have been on the phone with him for 20 minutes. He wanted four prescriptions. We went back and forth on all the issues, and he finally asked, 'Well, what would you do?' "

"I told him, 'Well, I'm not writing it for my family,'" Oken said. He knows that some doctors are keeping a supply for their own use but believes "that's not right, either."

The Centers for Disease Control and Prevention and the Infectious Diseases Society of America are each drawing up advice to practitioners on the issue of home stockpiles, spokesmen said this week. With no vaccine available yet, an abundant supply of Tamiflu is one of the few weapons public health agencies could wield to try to stop an emerging pandemic. Mathematical models published this summer by two research teams concluded that spread of a contagious new strain of influenza virus could be slowed or even stopped by widespread use of Tamiflu at the outbreak site. Other experts, however, think that even with unlimited quantities of the drug, this is unrealistic.

Human infections with the H5N1 strains are extremely rare -- but frequently fatal. Since late 2003, 118 people have contracted the disease and 61 have died. The most recent was a 48-year-old Thai man who died Wednesday. During the same period, 140 million domestic birds, mostly chickens, have been killed or culled in efforts to halt the spread of the virus.

H5N1 is transmitted easily among birds but is not easily passed between people -- and may never develop that capacity.

Tamiflu is taken once a day to prevent influenza or twice a day to lessen symptoms once infection has occurred.

Ironically, the drug's surging popularity comes as new research suggests that some of the H5N1 strains that have infected human beings are so virulent that conventional doses may not be effective. How the drug should be used in a pandemic -- or whether it would even work -- is uncertain.

Although some doctors in the Washington area are writing stockpile prescriptions for Tamiflu, they are reluctant to talk about it. Queries to 15 practitioners found none who said they prescribed the drug without a specific need.

Audrey P. Corson, a physician in Bethesda who has practiced for 20 years, agreed that "this is a tough issue." She said she firmly believes, however, "that you don't give out drugs without a sick patient." Her only exceptions have been for two or three patients traveling to Southeast Asia, where all 118 human cases of H5N1 influenza infection have occurred. She thinks practitioners should consider both public health and patients' desires when confronted with the requests.

"If there is an outbreak, we're going to have to rely on the CDC and state governments to put those drugs where we need them. And I don't want them in people's bathrooms," she said.

Nevertheless, retail pharmacies and pharmacy benefit managers have noticed the rising demand.

Express Scripts, which handles prescriptions for more than 50 million people, has seen "a spike" in orders for Tamiflu, said Raulo Frear, vice president for clinical evaluation and policy. The St. Louis-based company, whose clients include 16,000 private employers, labor unions, HMOs and government agencies, typically sees prescriptions for the drug rise in early fall. Many doctors prescribe a course of treatment for high-risk patients to have on hand once flu season begins.

Last year, Frear said, Tamiflu prescriptions rose for about a month starting in late September, then plateaued for more than two months before rising again when flu season began after the new year. This year, the rise began in early September and has not yet peaked.

From January through August, about 1.7 million prescriptions for Tamiflu were filled in the United States -- more than three times the 2004 total of 497,000 prescriptions according to IMS Health, a pharmaceutical information and consulting company.

The pharmacies in the 165 Giant Food stores in the Baltimore-Washington area have filled about 1,000 prescriptions for Tamiflu in the past three weeks, 10 times as many as in the same period last year.

"We're not in the flu season by any stretch of the imagination, so it appears to be some stockpiling. I don't know what other reason there would be for it," said Russell B. Fair, Giant's vice president for pharmacy operations.

Terence J. Hurley, a spokesman for Roche, the giant Swiss pharmaceutical house that makes Tamiflu, confirmed that "prescriptions are up considerably compared to last year at this time." Specific numbers were not available.

Roche is the only maker of Tamiflu, which takes more than six months to synthesize in a complicated and dangerous manufacturing process. The company said this week it is in discussions with four makers of generic drugs over possibly letting them produce Tamiflu, too.

Roche will soon start making the drug in the United States in an operation that involves six factories, the last approved for use on Monday by the Food and Drug Administration. Previously, Tamiflu was made only in Europe.

Hurley said about 40 countries have ordered Tamiflu, and the company expects to sell up to $270 million worth for national stockpiles in the second half of this year.

How many people those stockpiles could treat is a big question mark, however.

Experiments published in August by Hui-ling Yen, Elena A. Govorkova and others at St. Jude Children's Research Hospital in Memphis found that Tamiflu was much less useful against recent strains of H5N1 than it was against strains that circulated in Hong Kong in 1997.

Mice infected with a fatal strain of the virus circulating in Vietnam were given a five-day course of oseltamivir at amounts roughly equivalent to a human dose. Half died. In previous experiments, treated animals infected with the Hong Kong strain all survived. But when mice with the Vietnam virus were treated for a longer period -- eight days -- 80 percent survived.

washingtonpost.com