A report due out Monday from the Government Accountability Office also shows that the FDA has never pulled a drug off the market due to a lack of required follow-up about its actual benefits - even when such information is more than a decade overdue.

When pressed about that policy, agency officials said they have no plans to get more aggressive.

The GAO says the FDA should do more to track whether drugs approved based on preliminary results actually have lived up to their promise.

The FDA responded that the report paints an overly negative picture of its so-called "accelerated approval" program, which is only used to approve drugs for the most serious diseases.

"Millions of patients with serious or life-threatening illnesses have had earlier access to new safe and effective treatments," thanks to the program, the FDA said in its response to the report.

In 1992, the FDA began speeding up the approval of novel drugs based on so-called surrogate endpoints, or laboratory measures that suggest the drug will make real improvements in patient health. HIV drugs, for example, are cleared based on their virus-lowering power, a predictor of increased survival.

Drugmakers favor the program because it helps them get products to market sooner, without conducting long-term patient studies that can take years and cost hundreds of millions of dollars. A condition of quicker approvals is that drugmakers conduct follow-up studies to show the drug's benefits actually panned out.

But the GAO report, a copy of which was obtained by The Associated Press, identified several drugs still on the market that never lived up to their initial promise. And in the 16 years that the FDA has used accelerated approval, it has never once pulled a drug off the market due to missing or unimpressive follow-up data.

"FDA has fallen far short of where it should be for patient safety," said Sen. Charles Grassley, R-Iowa, who requested the investigation.

Of the 144 studies the FDA has required under the program since 1992, 64 percent have been completed and more than one-third are still pending, according to the GAO. Investigators said the FDA does not rigorously track whether companies are making progress on their required studies, although the agency is improving.

FDA officials say they have overhauled their tracking system since the GAO completed its report. And an outside analysis by contractor Booz Allen Hamilton concluded last month that most companies are meeting their study requirements on time.

But in the case of Shire Laboratories' low blood pressure treatment ProAmatine, the required study has gone incomplete for more than 13 years. The GAO found that ProAmatine has generated more than $257 million in sales, even though "the clinical benefit of the drug has never been established."

Mitochondrial genetic screening created

Published: Oct. 22, 2009 at 7:00 PM

SEATTLE, Oct. 22 (UPI) -- U.S. medical scientists say they've developed an innovative clinical diagnostic test to identify a wide range of mitochondrial disorders.

The scientists from the Seattle Children's Research Institute and the University of Washington said mutations to one of the mitochondrial genes, or to a number of nuclear genes with roles in mitochondrial function, can cause diseases which have very similar symptoms, making them difficult to diagnose and treat.

The researchers' new molecular diagnostic tool uses targeted genetic sequencing to screen a patient's DNA for variations in 362 genes that have been associated with mitochondrial disease or mitochondrial function.

They tested the tool by using it to screen three DNA samples. Two of the samples were taken from patients with mitochondrial disorders, who had been previously diagnosed by traditional sequencing methods, while the third came from a healthy individual. They said they found their new method was able to identify accurately the mutation underlying each patient's condition.

"Early and effective diagnosis (of mitochondrial disorders) is crucial for permitting appropriate management and accurate counseling," lead authors Jay Shendure and Sihoun Hahn said.

Hahn added: "Our study indicates that the use of next generation sequencing technology holds great promise as a tool for screening mitochondrial disorders."

The research is reported in the journal Genome Medicine.

WASHINGTON — Delfina Hernandez helped to carry out one of the most audacious drug research frauds in American history, but because federal drug regulators sent a legal notice years late and to the wrong address, she can legally continue to conduct research.

Ms. Hernandez was a study coordinator at the Southern California Research Institute, a drug testing operation in Whittier, Calif., that federal agents raided in 1997. The institute, which was led by Dr. Robert Fiddes, helped conduct more than 170 drug studies for nearly every major drug maker in the world and routinely falsified data and patient records while doing so.

Ms. Hernandez pleaded guilty to fraud, and federal law required the Food and Drug Administration to ban her from participating in further drug research. The agency had five years after her conviction in which to act.

But in a report scheduled for release on Thursday, Congressional investigators say the agency pays so little attention to its responsibilities to ban investigators convicted of fraud and is so disorganized about carrying them out that its actions take an average of four years to complete.

The agency did not send a notice to Ms. Hernandez until more than four years had passed, and then it went to the wrong address. When the agency realized its mistake, the ban against Ms. Hernandez could not take effect because time had run out.

Ms. Hernandez could not be reached for comment.

In a review of 18 proceedings, investigators for the Government Accountability Office found that the F.D.A. took from 1 to 11 years to complete its process to ban researchers. This means many who were convicted of fraud remained eligible to conduct experiments for years.

Anticipating the office’s findings, the drug agency released a statement saying it had improved the process with increased staffing and centralized coordination.

“The F.D.A. views any deviation from its high standards for developing or marketing drugs and devices as a potential threat to patient safety and public health,” said Norris Alderson, the agency’s associate commissioner for science. “We will take strong action against anyone who chooses to ignore or flout the legal requirements for the products we regulate.”

Representative Joe L. Barton of Texas, the senior Republican on the House Energy and Commerce Committee, criticized the drug agency’s slowness in banning fraudulent investigators. Mr. Barton noted the example of Dr. Anne Kirkman-Campbell, an Alabama doctor who participated in trials of Ketek, an antibiotic that has been linked to liver failure.

Dr. Kirkman-Campbell was among several Ketek investigators whose data were found to be fraudulent. She was prosecuted for mail fraud and pleaded guilty in 2003, but the F.D.A. did not ban her from taking part in drug tests until Sept. 2, 2008.

Dr. Kirkman-Campbell could not be reached for comment.

Mr. Barton said he would introduce legislation to give the agency more power to ban researchers convicted of fraud from later participating in any kind of human research.

“The problems at F.D.A. are daunting,” he said, “but I think that a little common sense and some modest legislating can ensure that American families will be safe.”

The American Cancer Society, which has long been a staunch defender of most cancer screening, is now saying that the benefits of detecting many cancers, especially breast and prostate, have been overstated.

It is quietly working on a message, to put on its Web site early next year, to emphasize that screening for breast and prostate cancer and certain other cancers can come with a real risk of overtreating many small cancers while missing cancers that are deadly.

“We don’t want people to panic,” said Dr. Otis Brawley, chief medical officer of the cancer society. “But I’m admitting that American medicine has overpromised when it comes to screening. The advantages to screening have been exaggerated.”

Prostate cancer screening has long been problematic. The cancer society, which with more than two million volunteers is one of the nation’s largest voluntary health agencies, does not advocate testing for all men. And many researchers point out that the PSA prostate cancer screening test has not been shown to prevent prostate cancer deaths.

There has been much less public debate about mammograms. Studies from the 1960s to the 1980s found that they reduced the death rate from breast cancer by up to 20 percent.

The cancer society’s decision to reconsider its message about the risks as well as potential benefits of screening was spurred in part by an analysis published Wednesday in The Journal of the American Medical Association, Dr. Brawley said.

In it, researchers report a 40 percent increase in breast cancer diagnoses and a near doubling of early stage cancers, but just a 10 percent decline in cancers that have spread beyond the breast to the lymph nodes or elsewhere in the body. With prostate cancer, the situation is similar, the researchers report.

If breast and prostate cancer screening really fulfilled their promise, the researchers note, cancers that once were found late, when they were often incurable, would now be found early, when they could be cured. A large increase in early cancers would be balanced by a commensurate decline in late-stage cancers. That is what happened with screening for colon and cervical cancers. But not with breast and prostate cancer.

Still, the researchers and others say, they do not think all screening will — or should — go away. Instead, they say that when people make a decision about being screened, they should understand what is known about the risks and benefits.

For now, those risks are not emphasized in the cancer society’s mammogram message which states that a mammogram is “one of the best things a woman can do to protect her health.”

Dr. Brawley says mammograms can prevent some cancer deaths. However, he says, “If a woman says, ‘I don’t want it,’ I would not think badly of her but I would like her to get it.”

But some, like Colin Begg, a biostatistician at Memorial Sloan-Kettering Cancer Center in New York, worry that the increased discussion of screening’s risks is going to confuse the public and make people turn away from screening, mammography in particular.

“I am concerned that the complex view of a changing landscape will be distilled by the public into yet another ‘screening does not work’ headline,” Dr. Begg said. “The fact that population screening is no panacea does not mean that it is useless,” he added.

The new analysis — by Dr. Laura Esserman, a professor of surgery and radiology at the University of California, San Francisco, and director of the Carol Frank Buck Breast Care Center there, and Dr. Ian Thompson, professor and chairman of the department of urology at The University of Texas Health Science Center, San Antonio — finds that prostate cancer screening and breast cancer screening are not so different.

Both have a problem that runs counter to everything people have been told about cancer: They are finding cancers that do not need to be found because they would never spread and kill or even be noticed if left alone. That has led to a huge increase in cancer diagnoses because, without screening, those innocuous cancers would go undetected.

At the same time, both screening tests are not making much of a dent in the number of cancers that are deadly. That may be because many lethal breast cancers grow so fast they spring up between mammograms. And the deadly prostate ones have already spread at the time of cancer screening. The dilemma for breast and prostate screening is that it is not usually clear which tumors need aggressive treatment and which can be left alone. And one reason that is not clear, some say, is that studying it has not been much of a priority.

“The issue here is, as we look at cancer medicine over the last 35 or 40 years, we have always worked to treat cancer or to find cancer early,” Dr. Brawley said. “And we never sat back and actually thought, ‘Are we treating the cancers that need to be treated?’ ”

The very idea that some cancers are not dangerous and some might actually go away on their own can be hard to swallow, researchers say.

“It is so counterintuitive that it raises debate every time it comes up and every time it has been observed,” said Dr. Barnett Kramer, associate director for disease prevention at the National Institutes of Health.

It was first raised as a theoretical possibility in the 1970s, Dr. Kramer said. Then it was documented in a rare pediatric cancer, but was dismissed as something peculiar to that cancer. Then it was discovered in common cancers as well, but it is still not always accepted or appreciated, he said.

But finding those insignificant cancers is the reason the breast and prostate cancer rates soared when screening was introduced, Dr. Kramer said. And those cancers, he said, are the reason screening has the problem called overdiagnosis — labeling innocuous tumors cancer and treating them as though they could be lethal when in fact they are not dangerous.

“Overdiagnosis is pure, unadulterated harm,” he said.

Dr. Peter Albertsen, chief and program director of the urology division at the University of Connecticut Health Center, said that had not been an easy message to get across. “Politically, it’s almost unacceptable,” Dr. Albertsen said. “If you question overdiagnosis in breast cancer, you are against women. If you question overdiagnosis in prostate cancer, you are against men.”

Dr. Esserman hopes that as research continues on how to advance beyond screening, distinguishing innocuous tumors from dangerous ones, people will be more realistic about what screening can do.

“Someone may say, ‘I don’t want to be screened’ ” she said. “Another person may say, ‘Of course I want to be screened.’ Just like everything in medicine, there is no free lunch. For every intervention, there are complications and problems.”

* Drug abuse chief eyes vaccines as new treatment option

* Nicotine vaccines could reach $2 billion market by 2016

By Julie Steenhuysen

CHICAGO, Oct 20 (Reuters) - Hooked on cocaine or cigarettes? The U.S. government wants drug companies to make a vaccine for that.

Convinced of the need for new and better treatments for addiction, the government is focusing its efforts on vaccine development as a new way to treat and possibly prevent addiction to a range of addictive substances.

"It's a perspective that is very different from what we've operated on in the past," Dr. Nora Volkow, director of the National Institute on Drug Abuse told reporters this week at the Society for Neuroscience meeting in Chicago.

Volkow said the agency intends to piggyback on the frenetic investment by drug companies in vaccine development, spurred by the need for new products and the runaway success of products like Merck's (MRK.N) Gardasil vaccine to prevent the virus that causes cervical cancer.

"There is an enormous amount of research and development in vaccines for cancers and a wide variety of disorders," she said. "We can take advantage of those developments."

But first Volkow has to tempt drug companies to develop the vaccines by funding costly clinical trials.

Earlier this month, her agency, part of the National Institutes of Health, awarded Nabi Biopharmaceuticals (NABI.O) a $10 million grant -- the agency's largest ever -- for a late-stage clinical trial of Nabi's vaccine for nicotine addiction called NicVAX.

Volkow said she did her homework before backing the Nabi vaccine to ensure it was significantly different from other products. "Nonetheless, when you are investing in something at this level, it can be very risky," she said.

The vaccine is meant to stimulate the immune system to make antibodies against nicotine, blocking its rewarding effects and helping to prevent relapse in smokers trying to quit.

TOUGH MARKET

A similar anti-smoking vaccine by Cytos Biotechnology (CYTN.S) and Swiss drugmaker Novartis (NOVN.VX) last week missed its main goal in a midstage study, leading some analysts to question whether it can make it to market.

"They are still looking at it but it has been very problematic," said Robert Wasserman, director of investment research at the investment banking firm Dawson James in Florida.

"Vaccines are really tough," he said. "It's not for the faint of heart." 

Still, if it works, a nicotine vaccine could have a huge impact, Volkow said. "It's an international problem that kills 5 million individuals every year across the world," she said.

The global market for smoking cessation is expected to reach $4.6 billion by 2016, and vaccines could account for $2 billion in sales, according to independent market research firm Datamonitor.

Volkow said the same methods for making a nicotine vaccine could be used for other illicit substances.

Her agency backed a study released this month of an anti-cocaine vaccine that helped block the high felt by 38 percent of addicts who took it.

The vaccine was developed by Dr. Thomas Kosten of Baylor College of Medicine in Houston, who used a similar approach to make a nicotine vaccine now being tested in Europe by private equity firm Celtic Pharma.

Volkow said drumming up drug company interest in vaccines for illicit drugs is a harder sell because of liability concerns, and the fact that drug abusers are stigmatized.

"Unfortunately, when it comes to treatments for drug addiction ... most of the investment goes to the government," she said. (Editing by Mohammad Zargham)

LONDON, Oct 19 (Reuters) - Some treatments for inflammatory bowel disease increase the risk of infection-related cancers, French scientists said on Monday, but the benefits of the drugs still outweigh the risks.

Thiopurine drugs -- immunosuppressive medicines that inhibit the body's immune system -- are regularly used to treat inflammatory bowel disease, the researchers said, but can increase the risk of cancers linked to viral infections.

Laurent Beaugerie and colleagues at the Saint-Antoine hospital in Paris looked at more than 19,000 patients with inflammatory bowel disease. Around 30 percent of the patients were taking thiopurines, 14 percent had stopped taking them and 56 percent had never taken them.

Following up after almost 3 years, the researchers found 23 new cases of cancers -- one of Hodgkin's lymphoma and 22 of non-Hodgkin lymphoma.

Statistical analysis showed that patients receiving thiopurines -- like azathioprine produced by several generic drugmakers and by GlaxoSmithKline (GSK.L) as Imuran -- had a more than five-fold increased risk of lymphoma compared with those who had never received the drugs, the researchers said in a study published in The Lancet journal.

Older male patients with a longer history of inflammatory bowel disease also had increased lymphoma cancer risk.

"The absolute cumulative risk...in young patients receiving a 10-year course of thiopurines remains low -- (less than 1 percent) -- and does not undermine the positive risk-benefit ratio of these drugs," the researchers wrote.

But for elderly patients and for unlimited treatment periods, more studies were needed to assess the risk, they said.

Commenting on the study, Geert D'Haens of the Imelda GI Clinical Research Centre and Paul Rutgeerts University Hospital Gasthuisberg, both in Belgium, said doctors should be cautious in prescribing thiopurines for prolonged periods.

But they said that despite the slightly increased risk of lymphoma, the drugs would "probably remain one of the cornerstones of treatment." (Reporting by Kate Kelland; Editing by Charles Dick)