, June 22, 2010, by Gardiner Harris, WASHINGTON — Medical ethicists have worried for years about the growing share of new drugs whose human trials took place in foreign countries where federal auditors could not make sure patients were protected, but no one knew how big the potential problem was.

But according to a report by Daniel R. Levinson, the inspector general of the Department of Health and Human Services, 80 percent of the drugs approved for sale in 2008 had trials in foreign countries, and 78 percent of all subjects who participated in clinical trials were enrolled at foreign sites.

The report is scheduled to be released publicly on Tuesday, but a copy was obtained by The New York Times.

Ten medicines approved in 2008 were tested entirely abroad with not a single test patient in the United States, the report said.

In many cases, foreign trials provide invaluable information proving that drugs are effective in a variety of ethnic groups. Mr. Levinson’s report found that most foreign clinical trial sites and subjects were in Western Europe, where ethical controls over research are generally as robust as those in the United States.

But the report found that Central and South America had the highest number of subjects per site and accounted for 26 percent of all subjects enrolled at foreign trial sites. In 2008, the Food and Drug Administration inspected 1.9 percent of domestic clinical trial sites, while just 0.7 percent of foreign clinical trial sites were similarly audited. Mr. Levinson’s investigators found that the F.D.A. was 16 times more likely to audit a domestic site than a foreign one.

Mr. Levinson pointed out that the agency was often unaware of foreign clinical trials as they were being conducted. As a result, federal regulators have no ability to ensure that patients in these trials are being protected while the research is continuing.

Instead, federal auditors can go back to the trial sites only after a company submits an application to sell the medicine in the United States — often years after the trial ceased.

Even among trials that are registered with the F.D.A. before they begin, the share of foreign investigators has more than doubled to roughly a third of investigators in 2008 from about 13 percent in 1998.

The report “highlights a very frightening and appalling situation,” said Representative Rosa DeLauro, Democrat of Connecticut. “By pursuing clinical trials in foreign countries with lower standards and where F.D.A. lacks oversight, the industry is seeking the path of least resistance toward lower costs and higher profits to the detriment of public health.”

The F.D.A. did not provide an immediate comment.

The agency has long been plagued by budget shortages in its inspectional program, and audits of foreign clinical trial sites are expensive, costing upwards of $40,000 each. An increasing share of drugs are tested at multiple sites, with each investigator having only a limited number of subjects. So the share of data that can be audited at a single site has declined, making audits less representative and less useful.

The agency has also been challenged by its own poor record-keeping and data submissions from drug makers that do not adhere to standardized formats. For instance, the F.D.A. was unable to provide Mr. Levinson’s investigators with detailed clinical trial data for 29 of the 129 of the approved applications in 2008. For eight of the applications, the agency could not locate any part of the application.

Mr. Levinson suggested that the agency demand that drug companies submit their applications in a standardized electronic format. A database controlled by the F.D.A. of foreign clinical trial sites would help identify sites and investigators for audits, he wrote.

“As sponsors increase the number of foreign clinical trials in support of F.D.A. marketing applications, the agency’s current method of using inspections to ensure human subject protections and data validity is becoming increasingly strained,” Mr. Levinson wrote.

To cope, he encouraged the F.D.A. to develop more cooperative inspection agreements with foreign governments, inspect more clinical trials in more countries and encourage companies to register their foreign trials before they are conducted.

In comments in the report, the agency largely agreed with Mr. Levinson’s suggestions and said it was testing a new computer system that would help track foreign clinical trial sites.

“I think this report just confirms the potential problems with foreign trials,” said Dr. Adil E. Shamoo, editor in chief of Accountability in Research, a journal about research ethics. “There is less liability, patient recruitment is far easier, the concept of informed consent is not well established, and it’s cheaper.”

Harvard Medical School, BOSTON, MA — Sudden cardiac arrest is a common and deadly event. Twenty percent of all deaths in the United States each year are due to a sudden cardiac arrest; barely 5% of people who have one survive. The perception of a sudden cardiac arrest is that it comes out of the blue, but a new study suggests that despite its name, it often has warning signs.

Studying cardiac arrest isn’t easy since it is generally fatal, and you can’t ask the victims how they felt before the attack. Interviewing witnesses can help, but that is often done much later. Researchers in Germany tried to fill in the blanks by asking doctors to interview witnesses on the spot. The doctors gathered information on 406 cases and found that warning signs were surprisingly common.

Chest pain, shortness of breath, nausea or vomiting, and dizziness were the most common heralds of an impending cardiac arrest. Some people began to experience these hours before the arrest. In 90% of the cases, symptoms lasted for at least five minutes. Only 25% of the victims had truly out-of-the-blue arrests that weren’t preceded by symptoms.

The Harvard Heart Letter recommends that you call 911 if you notice one or more of the signs below in yourself or someone else:

  • uncomfortable pressure, fullness, tightness, or pain in the chest
  • pain, numbness, or other uncomfortable sensations in one or both arms, the back, neck, jaw, or stomach
  • shortness of breath
  • sudden nausea or vomiting
  • lightheadedness
  • unusual fatigue
  • heat and flushing or cold sweat
  • sudden heaviness, weakness, or aching in one or both arms

Cardiac Arrest

The American Heart Association urges the public to be prepared for cardiac emergencies:

  • Know the warning signs of cardiac arrest. During cardiac arrest a victim loses consciousness, stops normal breathing and loses pulse and blood pressure.
  • Call 9-1-1 immediately to access the emergency medical system if you see any cardiac arrest warning signs.
  • Give cardiopulmonary resuscitation (CPR) to help keep the cardiac arrest victim alive until emergency help arrives. CPR keeps blood and oxygen flowing to the heart and brain until defibrillation can be administered.

What is cardiac arrest?

Cardiac arrest is the sudden, abrupt loss of heart function. The victim may or may not have diagnosed heart disease. It’s also called sudden cardiac arrest or unexpected cardiac arrest. Sudden death (also called sudden cardiac death) occurs within minutes after symptoms appear.

What causes cardiac arrest?

The most common underlying reason for patients to die suddenly from cardiac arrest is coronary heart disease. Most cardiac arrests that lead to sudden death occur when the electrical impulses in the diseased heart become rapid (ventricular tachycardia) or chaotic (ventricular fibrillation) or both. This irregular heart rhythm (arrhythmia) causes the heart to suddenly stop beating. Some cardiac arrests are due to extreme slowing of the heart. This is called bradycardia.

Other factors besides heart disease and heart attack can cause cardiac arrest. They include respiratory arrest, electrocution, drowning, choking and trauma. Cardiac arrest can also occur without any known cause.

Can cardiac arrest be reversed?

Brain death and permanent death start to occur in just 4 to 6 minutes after someone experiences cardiac arrest. Cardiac arrest can be reversed if it’s treated within a few minutes with an electric shock to the heart to restore a normal heartbeat. This process is called defibrillation. A victim’s chances of survival are reduced by 7 to 10 percent with every minute that passes without CPR and defibrillation. Few attempts at resuscitation succeed after 10 minutes.

How many people survive cardiac arrest?

No statistics are available for the exact number of cardiac arrests that occur each year. It’s estimated that more than 95 percent of cardiac arrest victims die before reaching the hospital. In cities where defibrillation is provided within 5 to 7 minutes, the survival rate from sudden cardiac arrest is as high as 30–45 percent.

What can be done to increase the survival rate?

Early CPR and rapid defibrillation combined with early advanced care can result in high long-term survival rates for witnessed cardiac arrest. For instance, in June 1999, automated external defibrillators (AEDs) were mounted 1 minute apart in plain view at Chicago’s O’Hare and Midway airports. In the first 10 months, 14 cardiac arrests occurred, with 12 of the 14 victims in ventricular fibrillation. Nine of the 14 victims (64 percent) were revived with an AED and had no brain damage.

If bystander CPR was initiated more consistently, if AEDs were more widely available, and if every community could achieve a 20 percent cardiac arrest survival rate, an estimated 40,000 more lives could be saved each year. Death from sudden cardiac arrest is not inevitable. If more people react quickly by calling 9-1-1 and performing CPR, more lives can be saved.

Shinya Yamanaka
Image: The Lasker Foundation

Stem cell researcher Shinya Yamanaka will receive this year’s Kyoto Prize in Advanced Technology for his work on generating pluripotent stem cells from adult tissues, the non-profit Inamori Foundation announced on June 18th.

In 2006, Yamanaka, currently a senior investigator at the Gladstone Institute of Cardiovascular Disease in San Francisco and a professor at Kyoto University, presented his work aimed at inducing pluripotency in somatic cells. Starting from a list of 100 proto-oncogenes and embryonic stem (ES) cell-associated transcripts, he and his colleagues at Kyoto University in Japan eventually whittled the list down to the four now-famed “Yamanaka factors,” which, when introduced with retroviruses into mouse fibroblasts, appeared to revert the cells back to an embryonic-like state. The names of the four factors were not revealed, however, until the research results were published in Cell that August.

Since then, Yamanaka’s team has made numerous advances in the field of iPS cell research, including developing a way to identify which cells have become pluripotent, and inducing pluripotency in epithelial cells from the livers and stomachs of adult mice and adult human skin cells. His team has also managed to eliminate one of the four factors (the c-Myc gene), which induces proliferation, thereby reducing the amount of tumor formation.

Yamanaka’s 2007 Cell paper was one of the most-cited papers last year, according to ISI. Last year, the No. 1 spot in The Scientist‘s Top 10 Innovations of 2009 went to a group that induced pluripotency in mouse embryonic fibroblast cells using only proteins, including the protein form of Yamanaka’s four transcription factors, avoiding genetic modification altogether.

Last year, Yamanaka shared the Albert Lasker Basic Medical Research Award for his work in reverting adult cells to an embryonic-like state.

Yamanaka will receive 50 million yen (US$555,000) at the Kyoto Prize presentation ceremony in Kyoto, Japan, this November.

And back in 2008 Yamanaka was hot on the trail……………read more 

Epithelial Cells Made Pluripotent

Posted by Bob Grant

Entry posted at 14th February 2008

A team of Japanese researchers has changed epithelial cells from the livers and stomachs of adult mice into pluripotent cells that resemble embryonic stem cells, according to a paper in this week’s Science.

In 2006, the Kyoto University team, led by Shinya Yamanaka, used retroviruses to transfect adult mouse fibroblasts and embryonic cells with four transcription factors, reprogramming them into pluripotent cells. Last year they used the technique to reprogram human fibroblasts into pluripotent stem cells, setting off a whirlwind of research attention focused on reprogramming fibroblasts into stem cells that might grow into specific tissues and organs for transplant.

But the current study suggests that stem cells generated from adult epithelial cells rather than adult fibroblasts may provide better raw material for patient-specific tissues and organs.

Lorenz Studer, of the Memorial Sloan-Kettering Cancer Center, said that the Yamanaka study may shift the stem cell research community’s focus on fibroblasts. “Everyone wanted to use fibroblasts,” he told The Scientist. “But people will now go back and ask, ‘Is this the right population to make patient-specific cells?'”

Yamanaka and his collaborators used retroviral vectors to introduce four transcription factors – Oct 3/4, Sox2. Klf4, and c-Myc – into mouse hepatic and gastric cells, and the resulting cells grew into several different cell types.

The authors compared epithelial cell-derived to fibroblast-derived pluripotent cells and found that the former were more similar to embryonic stem cells and were less likely to cause tumors in chimeric mice grown from the cells. This last feature appeared to result from the fact that pluripotent cells generated from liver or stomach cells needed only one to four specific insertion sites for each gene transfected via retrovirus, whereas reprogramming fibroblasts requires many more so-called integration sites. This increased retroviral integration can activate oncogenes and increase cancer risk in reprogrammed fibroblasts.

“If you can make [stem] cells with fewer integration sites, that would be the cell of choice to do pre-clinical trials in animals,” Studer, who was not involved with the Yamanaka study, said. That’s why “this paper is important for future reprogramming studies,” he added.

Read more: Epithelial cells made pluripotent – The Scientist – Magazine of the Life Sciences

Read more: Kyoto Prize goes to Yamanaka – The Scientist – Magazine of the Life Sciences

Peter Carmel MD, June 22, 2010, by Emma Hitt PhD   —  Peter W. Carmel, MD, a pediatric neurosurgeon practicing in New Jersey, has been named president-elect of the American Medical Association (AMA). He will take over the president’s role in June 2011 after serving a year as president-elect.

“In terms of my personal career, being elected to this position is, of course, the top of a career in organized medicine,” Dr. Carmel told Medscape Medical News in a telephone interview.

He added that, “I see this as a chance to lead the face of American medicine at a time when our Congress has not been mindful of the fact that doctors are being deprived of a livelihood under Medicare.”

His biggest responsibility as president of the AMA, he said, will be to represent American physicians to the public, to non-AMA physicians, to the press, and to Congress.

“I think that practically all doctors can agree on 2 things,” Dr. Carmel said. “Number one, that there was a great deal of gain for patients in the healthcare law, in terms of protecting their health insurance and in allowing access to care — so that’s good.”

However, he added that “the second thing I think that practically all doctors can agree on is that the healthcare law did not pay attention to the doctors’ agenda for what they needed fixed, in healthcare,” he said. “I think that my goal here is to represent physicians and to state their case as well as I can.”

I think that my goal here is to represent physicians and to state their case as well as I can.

Dr. Carmel is currently chairman of the Department of Neurological Surgery at the New Jersey Medical School and co–medical director of the Neurological Institute of New Jersey.

According to a written release from the AMA, Dr. Carmel was first elected to the AMA Board of Trustees in 2002 and was reelected in 2006. Dr. Carmel was a member of the AMA House of Delegates for 17 years and served as chair of the Specialty and Service Society and helped it gain AMA bylaws recognition.

From 2006 to 2007, Dr. Carmel served as president of the AMA Foundation and currently sits on its board of directors. He has also served in leadership roles with the American Association of Neurological Surgeons and the Congress of Neurological Surgeons.

Dr. Carmel has also served as chairman of the National Coalition for Research in Neurological Disease and Stroke, and subsequently as chair of the National Foundation for Brain Research. In 1969, he founded the Neuroendocrine Laboratory within the Institute for the Study of Human Reproduction at Columbia University College of Physicians and Surgeons, New York City.