Good Health And Wellness For Life

Whistle-Blower Is Awarded $1.6 Million

A former drug sales representative who became a whistle-blower has been awarded $1.6 million for bringing a drug marketing fraud to light, despite efforts by the Justice Department to prevent his receiving the money.

But in the same ruling, a federal judge criticized the former sales representative, James Marchese, for not bringing the scheme to light earlier, given that he thought that cancer patients were being harmed as a result of the fraud.

Mr. Marchese’s case, which was described in an October article in The New York Times, drew attention because prosecutors had rarely argued that a whistle-blower should be denied any portion of the funds recovered from a lawsuit he or she initiated.

To do so, prosecutors must show that a whistle-blower was the planner or initiator of the scheme involved; otherwise he or she is legally entitled to receive 15 to 25 percent of any funds recovered by the government. The precise figure is determined by a whistle-blower’s contribution to the case.

In a ruling after a two-day hearing last month in Seattle, Judge Marsha J. Pechman of Federal District Court found that prosecutors had failed to prove that Mr. Marchese was the initiator of a scheme at his former employer, Cell Therapeutics. In April, the company agreed to pay $10.5 million to settle charges that it had bilked Medicare out of that much money in connection with the sale of a cancer drug, Trisenox.

At the hearing, Mr. Marchese and his lawyers argued that he should receive 25 percent, about $2.6 million. Among other things, Mr. Marchese maintained that the government would never have had a case without him.

In her decision, which was issued last Friday, Judge Pechman awarded him the minimum 15 percent, or $1.6 million. She found that Mr. Marchese had helped prosecutors uncover the scope of the company’s fraud.

“Mr. Marchese provided the government with evidence of fraudulent activity that the government would not otherwise have discovered,” Judge Pechman wrote.

In a telephone interview Thursday, Mr. Marchese said he was pleased with the ruling. His lawyers said his 15 percent award was slightly less than the typical one, which is 17 percent.

“I think the court did a phenomenal job of getting around the issues,” Mr. Marchese said.

But the ruling also criticized him for not alerting federal authorities more quickly.

Instead, Mr. Marchese, passed over for a promotion, wrote an angry letter to his superiors, taking credit for the very actions that he thought were causing harm, Judge Pechman noted. It was not until October 2002, after another falling-out with his superiors, that he went to the Food and Drug Administration, she found.

In settling the charges against it, Cell Therapeutics did not admit to any wrongdoing, and continues to dispute the accusations. An assistant United States attorney in Seattle, Peter A. Winn, who handled the case, said that his office was pleased that Judge Pechman had limited the award to 15 percent.

Data About Zetia Risks Was Not Fully Revealed

New evidence shows that the drug makers Merck and Schering-Plough have conducted several studies of their popular cholesterol medicine Zetia that raise questions about its risks to the liver, but the companies have never published those results.

Partial results of the studies, alluded to in documents on the Food and Drug Administration’s Web site, raise questions about whether Zetia can cause liver damage when used long term with other cholesterol drugs called statins.

Most of the millions of people who use Zetia take it along with a statin like Lipitor, Crestor or Zocor. Or they take it in a single pill, Vytorin, that combines Zetia with Zocor.

The discovery of the unpublished research comes as Merck and Schering are already under criticism for not yet releasing data from an important Zetia study, called Enhance, that they completed early last year.

The Enhance data may also contain important information about Zetia’s liver risks. At least some patients were dropped from the Enhance study after testing revealed that they had elevated liver enzymes, a Schering-Plough spokesman confirmed this week.

But a full report on that trial, including the number of patients who had liver problems, will not be available until March.

Doctors say that by failing to disclose promptly all their research, Merck and Schering-Plough may be leaving the public with a misleadingly favorable view of Zetia’s safety and benefits.

“You don’t want to have data missing,” said Dr. Bruce Psaty, a professor of medicine and epidemiology at the University of Washington. “When there have been adverse effects, when the benefits don’t look impressive, those are the trials that historically don’t make it to press.”

A Schering executive, when asked by a reporter about the unpublished studies, confirmed their existence. But the executive, Dr. Robert J. Spiegel, said the companies had not considered the studies scientifically important enough to publish their findings. Some may eventually be published, he said.

“We’re pretty comfortable that people don’t have trouble tolerating Zetia,” said Dr. Spiegel, the chief medical officer of the Schering-Plough Research Institute, Kenilworth, N.J.

Schering also said that the F.D.A. had reviewed the data from the unpublished studies and had approved Zetia for use alongside statins. But experts on drug safety say that the agency has been slow to issue warnings about many widely used drugs that have turned out to carry serious risks, including the painkiller Vioxx, the diabetes medicine Avandia and the anti-psychotic drug Zyprexa.

Even doctors critical of Zetia generally say it is safe for most patients. But before the drug was approved in 2002, one F.D.A. reviewer said it should not be cleared for use with statins because the combination had caused liver damage in animals. And in the last two years, scattered case reports of severe liver damage in patients taking Zetia in combination with statins have appeared in medical journals.

In the United States, the product label for Zetia contains only mild warnings about the drug’s potential for liver damage.

But in Australia and Canada, regulators have been more cautious. Since 2005, they have issued a series of warnings about Zetia’s potential to cause hepatitis, pancreatitis and depression — warnings that have largely gone unnoticed in the United States.

All drugs have potential risks and side effects, of course, and doctors and patients must weigh those against a drug’s medical benefits. But in the case of Zetia, despite its widespread use, there is no evidence proving that Zetia can reduce heart attacks and strokes, as cholesterol drugs are meant to do. There is extensive medical evidence showing that Lipitor and other statins provide such protection.

The unpublished Zetia studies, devised as safety tests, would not prove the drug’s effectiveness. But they would give the public more information about Zetia’s potential risks. All the unpublished studies covered periods at least one year in length and were intended to show whether long-term use of Zetia might pose dangers that short-term use did not.

Most of the studies about Zetia in which Merck and Schering have published the results covered periods of only 12 weeks — not enough time for liver problems to develop in most patients.

The unpublished studies, conducted from 2000 to 2003 according to the F.D.A. documents, were not listed on the industry Web sites where companies are supposed to register the results of all drug trials that were ongoing after October 2002. The New York Times discovered references to the studies in briefing papers on the F.D.A. Web site.

“We keep telling people we want to practice evidence-based medicine, and what we keep finding out is that much of the evidence is obscured,” said Dr. Harlan Krumholz, a cardiologist at Yale, when told about the previously undisclosed studies. “There is important evidence, but it’s not in public view. It’s hidden from investigators.”

Schering and Merck — which are on track to earn $5 billion this year from sales of Zetia — had already been criticized for not promptly releasing results of the Enhance trial, which was completed in April 2006. Under pressure from Congress and prominent cardiologists, the companies said recently that they would release the full results of the Enhance trial by March.

In response to questions from The Times, the Schering spokesman, Lee Davies, disclosed this week that some patients in the Enhance trial had been dropped from it after tests showed that they had elevated liver enzymes — a potential sign of organ damage. But Mr. Davies said he could not disclose how many, and said the companies did not even know if the patients who had been dropped were taking Zetia and a statin, or just a statin. The delay in releasing the Enhance trial data is unrelated to the patients who were discontinued, Mr. Davies said.

The Enhance data are expected to provide the clearest picture yet of Zetia’s long-term affects. But the F.D.A.’s documents show that Merck and Schering conducted several other long-term trials of Zetia without releasing their findings.

Together those studies cover several thousand patients who took Zetia along with statins for one to two years. The statins include Lipitor and Crestor, as well as Zocor, which is usually prescribed generically as simvastatin and is the statin used in the Vytorin pill. Doctors often add Zetia to a low dosage of a statin, because Zetia reduces cholesterol in a different way than the statins do and leads to deeper overall cholesterol reductions.

One open question is whether Zetia’s method of lowering cholesterol provides the same medical benefits as fighting cholesterol with a higher-dose statin by itself. Last year, Merck and Schering began a separate study — a 10,000-patient clinical trial to prove that Zetia’s ability to lower cholesterol will translate into fewer heart attacks and strokes in patients. But data from that trial will not be available until at least 2011.

In the meantime, some doctors say, they must essentially take on faith that Zetia’s cholesterol-lowering ability will translate into real-world benefits and that its long-term use with statins does not have major risks.

Dr. Eric J. Topol, a cardiologist and director of the Scripps Translational Science Institute in La Jolla, Calif., said that he had asked Merck and Schering more than four years ago to conduct a large, long-term trial to prove that Zetia could reduce heart attacks and strokes. But the companies had little interest, he said.

“They looked at me like I was an alien,” Dr. Topol said.

Two months ago, President Bush signed a new law intended to strengthen penalties for companies that do not release information promptly. And in 2004, the drug industry promised to improve disclosure of research results.

But the new law applies only to new trials, meaning the unpublished Zetia trials are not covered by those new rules and guidelines.

The F.D.A. has reviewed the unpublished studies, according to the agency’s briefing papers.

The companies’ own published studies have generally played down the risk of liver problems. But Dr. Mark Stolk, a gastroenterologist in the Netherlands, last year reported two cases of patients who had developed hepatitis, a liver disease, after taking Zetia alongside Lipitor. One of the patients has since died, Dr. Stolk said in an interview last month. While Zetia is safe for most patients, doctors should carefully monitor patients for liver damage, he said.

“I think other cases will emerge,” he said.

When the F.D.A. approved Zetia in 2002, it relied on trials that covered only 3,900 patients and lasted no more than 12 weeks. Still, the data from even those trials contained signals that Zetia might be dangerous in some patients when it is taken alongside statins, as it usually is.

In those trials, 11 times as many people who took Zetia along with a statin subsequently had serious health problems, compared with those who took a statin alone. Nearly all the serious problems were liver-related. Still the F.D.A. regarded the risks as relatively minor and approved Zetia without asking the companies to conduct longer trials.

The agency did not respond to requests for comment.

All drugs have risks, of course. Doctors who prescribe Zetia say that while they would prefer to see long-term trial data, they are comfortable using it because decades of evidence demonstrated that lowering LDL, or so-called bad cholesterol, is good for patients.

But Dr. Beatrice A. Golomb, an associate professor at the University of California, San Diego, said doctors have lost sight of the purpose of prescribing drugs like Zetia.

The goal of prescribing cholesterol-lowering drugs is not reducing cholesterol, Dr. Golomb said. It is reducing the number of deaths and heart attacks in patients, he said. And without data to prove that Zetia actually reduces heart attacks, doctors cannot be sure they are helping patients when they prescribe the drug, she said.

Drug Maker and Eye Doctors Settle Dispute Over Avastin

Genentech appears to have resolved a dispute with ophthalmologists that will allow the company’s drug Avastin to continue to be used to treat eye diseases, both sides announced on Thursday.

Genentech infuriated many eye doctors in October when it announced a change in the distribution of Avastin that would have made it difficult for the doctors to use the drug. The doctors accused the company of trying to force them to use a much more expensive Genentech drug, Lucentis, instead.

Lucentis is approved to treat macular degeneration, a leading cause of blindness among the elderly.

But it costs about $2,000 for each injection into the eye, and injections are needed as often as once a month.

Many ophthalmologists are instead resorting to off-label use of Avastin, which is approved only to treat cancer but works in the same way as Lucentis. The eye doctors have been relying on compounding pharmacies to divide a vial of Avastin meant for cancer treatment into tiny portions for use in the eye under sterile conditions. In the tiny doses, Avastin costs $20 to $100 an injection.

But Genentech said in October that it would no longer sell Avastin to compounding pharmacies, which specialize in mixing drugs.

That prompted an inquiry by Senator Herb Kohl, Democrat of Wisconsin, chairman of the Special Committee on Aging. In letters requesting documents from Genentech, Medicare and the Food and Drug Administration, Mr. Kohl said the use of Lucentis instead of Avastin could cost Medicare $1 billion to $3 billion a year.

But on Thursday, Genentech and two societies of eye doctors announced that doctors would be able to purchase Avastin themselves and have the drug delivered to compounding pharmacies.

That would allow them access to the Avastin but would also enable Genentech to stop selling the drug to compounding pharmacies as of Jan. 1. The company has said that its sales to the pharmacies provoked concern at the F.D.A. because Avastin was not manufactured for use in the eye.

In a joint e-mail message sent to their members on Thursday, the American Academy of Ophthalmology and the American Society of Retina Specialists said they believed that the plan addressed “the needs of most of their members.”

The message cautioned, however, that some states might have regulations that would make it difficult to use this new arrangement.

Genentech and the societies also agreed to work together to improve Genentech’s programs for helping patients pay for Lucentis, the more expensive drug, or to find ways to provide it free to those who cannot pay. They also said they would work together to expedite reimbursement to doctors, who generally buy the Lucentis themselves and must wait to recover the outlay from patient bills or insurers.

Scientists Weigh Stem Cells’ Role as Cancer Cause

Within the next few months, researchers at three medical centers expect to start the first test in patients of one of the most promising — and contentious — ideas about the cause and treatment of cancer.

The idea is to take aim at what some scientists say are cancerous stem cells — aberrant cells that maintain and propagate malignant tumors.

Although many scientists have assumed that cancer cells are immortal — that they divide and grow indefinitely — most can only divide a certain number of times before dying. The stem-cell hypothesis says that cancers themselves may not die because they are fed by cancerous stem cells, a small and particularly dangerous kind of cell that can renew by dividing even as it spews out more cells that form the bulk of a tumor. Worse, stem cells may be impervious to most standard cancer therapies.

Not everyone accepts the hypothesis of cancerous stem cells. Skeptics say proponents are so in love with the idea that they dismiss or ignore evidence against it. Dr. Scott E. Kern, for instance, a leading pancreatic cancer researcher at Johns Hopkins University, said the hypothesis was more akin to religion than to science.

At stake in the debate is the direction of cancer research. If proponents of the stem-cell hypothesis are correct, it will usher in an era of hope for curing once-incurable cancers.

If the critics are right, the stem-cell enthusiasts are heading down a blind alley that will serve as just another cautionary tale in the history of medical research.

In the meantime, though, proponents are looking for ways to kill the stem cells, and say that certain new drugs may be the solution.

“Within the next year, we will see medical centers targeting stem cells in almost every cancer,” said Dr. Max S. Wicha, director of the University of Michigan Comprehensive Cancer Center, one of the sites for the preliminary study that begins in the next few months (the other participating institutions are Baylor College of Medicine in Houston and the Dana-Farber Cancer Institute in Boston).

“We are so excited about this,” Dr. Wicha said. “It has become a major thrust of our cancer center.”

At the National Cancer Institute, administrators seem excited, too.

“If this is real, it could have almost immediate impact,” said Dr. R. Allan Mufson, chief of the institute’s Cancer Immunology and Hematology Branch.

The cancer institute is financing the research, he said, and has authorized Dr. Mufson to put out a request for proposals, soliciting investigators to apply for cancer institute money to study cancer stem cells and ways to bring the research to cancer patients. The institute has agreed to contribute $5.4 million.

“Given the current fiscal situation, which is terrible, it’s a surprising amount,” Dr. Mufson said. “We actually asked for less,” he added, but the cancer institute’s executive committee asked that the amount be increased.

Proponents of the hypothesis like to use the analogy of a lawn dotted with dandelions: Mowing the lawn makes it look like the weeds are gone, but the roots are intact and the dandelions come back.

So it is with cancer, they say. Chemotherapy and radiation often destroy most of a tumor, but if they do not kill the stem cells, which are the cancer’s roots, it can grow back.

Cancerous stem cells are not the same as embryonic stem cells, the cells present early in development that can turn into any cell of the body. Cancerous stem cells are different. They can turn into tumor cells, and they are characterized by distinctive molecular markers.

The stem-cell hypothesis answered a longstanding question: does each cell in a tumor have the same ability to keep a cancer going? By one test the answer was no. When researchers transplanted tumor cells into a mouse that had no immune system, they found that not all of the cells could form tumors.

To take the work to the next step, researchers needed a good way to isolate the cancer-forming cells. Until recently, “the whole thing languished,” said Dr. John E. Dick, director of the stem cell biology program at the University of Toronto, because scientists did not have the molecular tools to investigate.

But when those tools emerged in the early 1990s, Dr. Dick found stem cells in acute myelogenous leukemia, a blood cancer. He reported that such cells made up just 1 percent of the leukemia cells and that those were the only ones that could form tumors in mice.

Yet Dr. Dick’s research, Dr. Wicha said, “was pretty much ignored.” Cancer researchers, he said, were not persuaded — and even if they had accepted the research — doubted that the results would hold for solid tumors, like those of the breast, colon, prostate or brain.

That changed in 1994, when Dr. Wicha and a colleague, Dr. Michael Clarke, who is now at Stanford, reported finding cancerous stem cells in breast cancer patients.

“The paper hit me like a bombshell,” said Robert Weinberg, a professor of biology at M.I.T. and a leader in cancer research. “To my mind, that is conceptually the most important paper in cancer over the past decade.”

Dr. Weinberg and others began pursuing the stem-cell hypothesis, and researchers now say they have found cancerous stem cells in cancers of the colon, head and neck, lung, prostate, brain, and pancreas.

Symposiums were held. Leading journals published paper after paper.

But difficult questions persisted. One problem, critics say, is that the math does not add up. The hypothesis only makes sense if a tiny fraction of cells in a tumor are stem cells, said Dr. Bert Vogelstein, a colon cancer researcher at Johns Hopkins who said he had not made up his mind on the validity of the hypothesis.

But some studies suggest that stem cells make up 10 percent or even 40 percent or 50 percent of tumor cells, at least by the molecular-marker criterion. If a treatment shrinks a tumor by 99 percent, as is often the case, and 10 percent of the tumor was stem cells, then the stem cells too must have been susceptible, Dr. Vogelstein says.

Critics also question the research on mice. The same cells that can give rise to a tumor if transplanted into one part of a mouse may not form a tumor elsewhere.

“A lot of things affect transplants,” Dr. Kern, the Johns Hopkins researcher, said, explaining that transplanting tumors into mice did not necessarily reveal whether there were stem cells.

Other doubts have been raised by Dr. Kornelia Polyak, a researcher at the Dana-Farber Cancer Institute. Dr. Polyak asked whether breast cancer cells remain true to type, that is, whether stem cells remain stem cells and whether others remain non-stem cells? The answer, she has found, is “not necessarily.”

Cancer cells instead appear to be moving targets, changing from stem cells to non-stem cells and back again. The discovery was unexpected because it had been thought that cell development went one way — from stem cell to tumor cell — and there was no going back.

“You want to kill all the cells in a tumor,” Dr. Polyak said. “Everyone assumes that currently-used drugs are not targeting stem cell populations, but that has not been proven.”

“To say you just have to kill the cancer stem cell is oversimplified,” she added. “It’s giving false hope.”

The criticisms make sense, Dr. Weinberg said. But he said he remained swayed by the stem cell hypothesis.

“There are a lot of unanswered questions, mind you,” he said. “Most believe cancer stem cells exist, but that doesn’t mean they exist. We believe it on the basis of rather fragmentary evidence, which I happen to believe in the aggregate is rather convincing.”

Dr. Wicha said he was convinced that the hypothesis was correct, and said it explained better than any other hypothesis what doctors and patients already know.

“Not only are some of the approaches we are using not getting us anywhere, but even the way we approve drugs is a bad model,” he said. Anti-cancer drugs, he noted, are approved if they shrink tumors even if they do not prolong life. It is the medical equivalent, he said, of mowing a dandelion field.

He said the moment of truth would come soon, with studies like the one planned for women with breast cancer.

The drug to be tested was developed by Merck to treat Alzheimer’s disease. It did not work on Alzheimer’s but it kills breast cancer stem cells in laboratory studies, Dr. Wicha says.

The study will start with a safety test on 30 women who have advanced breast cancer. Hopes are that it will be expanded to find out if the drug can prolong lives.

“Patient survival,” Dr. Wicha said, “is the ultimate endpoint.”

Some Lawyers Seek Changes in Vioxx Settlement

Several plaintiffs’ lawyers have asked the federal judge overseeing the $4.85 billion Vioxx settlement to give them the freedom to keep some of their clients outside the settlement while still allowing other clients to accept it.

Currently, if the lawyers want any of their clients to receive money from the settlement, they must recommend the deal to all their clients.

That provision was considered a crucial part of the settlement by Vioxx’s maker, the drug company Merck.

In an emergency motion with Judge Eldon E. Fallon of Federal District Court in New Orleans, the lawyers said the provision would prevent them from offering the best independent judgment for each client. Agreeing to the provision might open them to future lawsuits from disgruntled clients, they said.

“The Settlement Agreement, which allows Merck to dictate the advice a lawyer will offer, is improper in all states,” the lawyers wrote in the motion, which was filed Monday.

Grant Kaiser, a Houston lawyer who represents about 1,800 plaintiffs, filed the motion. It was co-signed by 11 other firms that collectively represent another 4,200 plaintiffs — about 10 percent of all the people who have sued Merck over Vioxx. Mr. Kaiser declined to comment on the motion.

Merck and several large plaintiffs’ law firms agreed to the settlement last month as a way to resolve more than 50,000 claims from people who assert that Vioxx, a painkiller that was pulled from the market in 2004, caused them to suffer heart attacks and strokes. Merck had won most of the 18 suits that reached juries in both state and federal court.

The requirement that lawyers agree to recommend the deal to all their clients — and withdraw from representing those who do not agree — is a crucial part of the agreement.

Merck wants lawyers to put all their clients into it so that it will not face the prospect that they will settle their weaker claims while withholding their stronger cases for trial in the future. Merck also wants to be sure that plaintiffs who do choose to go ahead will have to find new lawyers, a process that will probably be difficult because the firms with the most experience in the case are all part of the agreement.

“We knew this was a key component, a primary component of the settlement,” said Andy Birchfield, an Alabama lawyer whose firm began suing Merck over Vioxx in 2001. “It had to be a case where the lawyers were not cherry picking.”

For the deal to take effect, 85 percent of all plaintiffs, as well as 85 percent of plaintiffs who have stronger cases because they took the drug continuously for more than a year, must agree to its terms.

But Benjamin Zipursky, a professor at Fordham Law School who has closely followed the case, said the all-or-nothing requirement might pose ethical problems.

“The question is, is this really independent advice given to each client if the lawyer obligates himself or herself to say this to all the clients,” Mr. Zipursky said.

But Mr. Birchfield and other lawyers who have agreed to the deal said they had good reasons to accept the requirement. As a practical matter, plaintiffs will not be well served by bringing cases to court, given Merck’s strong record, said Christopher A. Seeger, a plaintiffs’ lawyer who was on the negotiating committee that helped devise the deal.

“We’ve tried 18 of these cases and these plaintiffs have lost of most of them,” Mr. Seeger said.

The motion will be heard in mid-January.