Recently approved, Exubera is the first in a line up of needle-free insulins promising to win the hearts of diabetics. Amidst all the hype, some market analysts predict it will be a blockbuster, while others believe it has been overvalued. Many industry experts are also being cautious.

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By January W. Payne

Before she died last month, Coretta Scott King turned to a Mexican alternative medicine clinic for treatment -- never begun -- of her stage III ovarian cancer. Whatever her reasons, with that move, the widow of slain civil rights icon Martin Luther King Jr. spotlighted a grim truth, say cancer...

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washingtonpost.com

WASHINGTON -- A new study of medicines prescribed in the U.S. has found that many patients are told to use drugs with "black box" warnings even though those drugs aren't suitable for their medical needs.

In a study to be published in today's Archives of Internal Medicine, researchers led by Cambridge Health Alliance and Harvard Medical School looked at outpatient prescriptions given by Boston-area medical clinics.

After examining the health records of 324,548 outpatients who received at least one prescription from Jan. 1 to Dec. 31, 2002, researchers found that 33,778 patients were prescribed a medication that had a black-box warning -- the Food and Drug Administration's strictest warning.

Black-box warnings are often at the top of a drug's label and are featured in the Physicians' Desk Reference, a guide used by health- care professionals that contains drug labels.

The black boxes highlight important drug guidelines, such as not allowing a particular drug to be prescribed with other drugs or to patients with certain medical conditions.

Of the 33,778 prescriptions, 2,354 were written in violation of a black-box warning. About 90% of the violations involved patients who had a disease for which use of the drug wasn't recommended. About 1,000 patients also were taking a drug that could have interacted with the black-box drug. Researchers noted that, in some cases, physicians may have chosen to purposely override a black-box warning.

The study found that patients who were female, older than 75 and took several medications were more likely to be given a drug in violation of its black-box warning.

While the figures show the number of patients who received a drug against the black-box warning is relatively small, compared with the total number of outpatient prescriptions dispensed in the study, "the absolute number of outpatients at risk is substantial," researchers wrote.

Researchers said one solution for cutting down on medical errors would be for the FDA to "make these warnings more specific so they are more readily understandable by [health-care] providers."

Wall Street Journal. (Eastern edition). New York, N.Y.: Feb 14, 2006. pg. D.7

MEI LI, a retired Shanghai warehouse worker with heart disease, had tried acupuncture and other treatments in an unsuccessful effort to lose weight. Then she volunteered to participate in a clinical trial for a new drug after spotting an advertisement in a local newspaper.

After taking a placebo for six months -- a common practice where a portion of participants unknowingly act as a control group -- the 62- year-old was given the weight-loss drug Xenical, made by Swiss pharmaceuticals company Roche Holding AG, for another six-month period. She lost 15.4 pounds.

By participating in clinical trials that test drugs' safety and efficcacy, Ms. Mei is among a growing number of Chinese patients receiving free access to Western medicine. Pharmaceutical companies benefit, too, with the prospect for sales in the world's biggest potential market and the opportunity to conduct trials at a fraction of the cost in the U.S. or Europe.

In many trials in China, the drugs being tested have been approved in the West -- Xenical has been available by prescription in the U.S. since 1999. Chinese authorities, however, want trials conducted in their own country before allowing the drugs to be sold.

Yet Ed Ikeguchi, chief medical officer of New York-based Medidata Solutions Inc., which develops software to evaluate data gathered in clinical trials, says some Chinese government officials told him they worry they will be "bullied" by Western companies into conducting risky trials for new drugs that wouldn't be allowed elsewhere.

Dr. Ikeguchi is working with Chinese officials to come up with standard methods of gathering data. He says some officials are concerned that as more trials are conducted in China, smaller drug companies may enter the market and attempt to cut corners in their trials for new drugs. Government officials think, " 'If you can do it so cheap, why not use a protocol you would not use elsewhere, exposing patients to risks?' " he says.

Roche, Eli Lilly & Co. of the U.S., AstraZeneca PLC of the United Kingdom, and other pharmaceutical companies say they follow World Health Organization guidelines to protect patients in clinical trials. The WHO guidelines are broadly equivalent to those used in the U.S., Europe, Canada and Japan. Patients sign informed-consent forms as they do in the U.S.

The Chinese government controls one important part of the clinical trials -- it licenses the physicians who decide how the trial is conducted and how data are gathered, and who hire fellow doctors to lead the trials and recruit patients. Drug companies fund the trials, provide the medicine and offer input on the goals of the trials.

Still, clinical-trial regulation in China is relatively new. China's State Food and Drug Administration was created in 2003, and one of the agency's first steps was to overhaul China's clinical practices, conducting audits and creating a database of physicians certified to do the research. Creating rules of ethics for foreign drug companies is planned. "There weren't any systems for quality assurance in the clinical-trials process until the creation of the regulatory agency," Dr. Ikeguchi says. Drug companies' clinical trials, in general, have gone smoothly in China.

While pharmaceuticals sales in China lag behind other regions, they are expected to jump to sixth place globally by 2015, up from ninth place, according to the Boston Consulting Group. As Western drug companies plot strategies to tap that market, many are basing clinical trials in China. Roche has at least five trials in Shanghai listed on Thomson Corp.'s CenterWatch, a drug-trial listing service based in Boston. Eli Lilly, Novartis AG of Switzerland, France's Sanofi-Aventis SA, and AstraZeneca, among others, also are conducting trials in China.

India has also become a center for clinical trials. Some universities in that country offer a master's degree in business administration with a concentration in clinical trials, says Sanjiv Malik, president of the Indian Medical Association.

Clinical trials are cheaper for drug companies in China than in Europe or in the U.S in part because of extensive regulations. Although many trials in China center on drugs previously approved in other parts of the world, others are for medicines in late-stage development -- so they have been deemed safe enough to test on large numbers of patients. While he was still AstraZeneca's chief executive, Tom McKillop noted at a conference last year that a major post- marketing clinical trial for two cardiovascular drugs -- involving 46,000 patients in 1,250 hospitals in China -- cost $3 million. "Could you do it in Europe?" at such a low cost, asked Mr. McKillop, now chairman of Royal Bank of Scotland PLC. "I don't think so."

Three-part clinical trials in China cost an average of a third of equivalent studies in the U.S., estimates Mark Engel, chief executive of Excel PharmaStudies Inc., of Beijing, China's largest clinical- research firm. For a Phase II trial, the cost for 100 patients in China could be as low as $25,000, while in the U.S. or Europe it could range from $500,000 to $1 million, according to Dr. Ikeguchi of Medidata Solutions.

Companies also have a hard time recruiting patients in developed countries who are wary of untried drugs. In China, there are lower hidden costs in clinical trials, such as fewer days needed to recruit patients, Mr. Engel says. Chinese patients also were initially resistant to drug trials, says Weifeng Shen, head of the cardiology department at Shanghai's Ruijin Hospital. "People thought that it would hurt them because it was an experiment," he says. "But now drug tests are being done frequently, and patients have become familiar with them." Plus, more patients in China are willing to enter clinical trials for the free Western medicine -- at least it's free for a certain amount of time, says Steen Kroyer, chairman of AstraZeneca's Chinese unit.

But at the end of a trial, many Chinese patients can't afford to buy the drugs to continue treatment -- which pharmaceutical companies don't feel undermine their trials because they see China as a long- term investment. Patients in trials are likely to be "significant users" of the drugs if prices come down, says Mr. Engel of Excel PharmaStudies. Yet only about 500 million Chinese have health insurance, with the country's remaining 800 million people relying on traditional healers or over-the-counter therapies. When she stopped taking Xenical, Ms. Mei, who lives on a modest pension, regained the weight.

Still, Ms. Mei says she was satisfied with the trial. After signing a voluntary consent form, she was given a diet to follow in addition to free medicine for the trial. Once a week, part-time Roche health educators, mostly university students, checked her eating and living habits. They suggested behavioral changes such as exercising more and eating fewer sweets. She also visited a hospital, designated by Roche, for blood-pressure tests and for treatment for heart-related health problems.

Wall Street Journal. (Eastern edition). New York, N.Y.: Feb 14, 2006. pg. B.1

A NEW ANALYSIS of a government study of menopause hormones provides the strongest evidence to date that estrogen doesn't pose a heart risk to younger women and may even offer additional protection.

The findings, published yesterday in the Archives of Internal Medicine, raise questions about whether government officials have overstated health concerns about menopause hormones since releasing results of the Women's Health Initiative in July 2002. At the time, their warnings about heart attack and breast cancer risks associated with menopause hormones prompted concern among women using the drugs.

However, a growing number of researchers, including many Women's Health Initiative investigators, have said the overall study results likely apply only to older women long past menopause and shouldn't be used to advise younger women seeking hormone treatment for the symptoms of menopause. At the time many of the initial study results were released, the detailed age breakdown of hormone users wasn't available.

Jacques Rossouw, project officer for the Women's Health Initiative, who first announced the initial results nearly four years ago, said the latest news should reassure women who are considering the drugs to treat menopause symptoms.

The new analysis of the data focused on the women who used only estrogen. The study, funded by the National Institutes of Health, supports the theory that age and timing of menopause hormones makes a difference in terms of the risks and benefits. Overall, estrogen use didn't pose a risk or benefit to a woman's heart. But when the results were broken down by age, the data showed that the youngest women in the study who used estrogen had a 45% lower risk for needing bypass surgery or angioplasty -- two key indicators of the women's heart health. The vast majority of the data from the initiative's studies has not been statistically meaningful, but the heart benefit to young women reported in the new analysis did meet that scientific threshold, giving the finding added credibility.

The data showed women who start hormones between the ages of 50 to 59, which is typically within 10 years of menopause, likely received heart protection from using the drugs. But estrogen users who started the drugs past the age of 60 didn't show any of the benefit reported by the younger users, and by the age of 70, heart risk appeared to increase.

The study didn't evaluate stroke or blood-clot risks of estrogen use or estrogen plus progestin. However, other analyses also have shown that the risk of those problems also is low for younger women.

The results are the latest piece of an increasingly complicated hormone puzzle. Many women and doctors have been confused by recent hormone news that seems to conflict with earlier research, but the fact is that the data have been remarkably consistent with the notion that timing of hormone use makes a difference in risks and benefits. Younger women who use the drugs at the onset of menopause likely face fewer risks and more benefits. But the drugs are far riskier if started in older women long past menopause. A study last month in the Journal of Women's Health reanalyzed data from the Nurses Health Study that began in 1976. That also showed that nurses who began hormone therapy near menopause had about a 30% lower risk for heart disease than women who didn't use hormones. By comparison, older nurses who started taking hormones at least 10 years after menopause didn't have any benefit.

Harvard Medical School researcher JoAnn Manson, co-author of both recent hormone analyses, said even though the studies suggest a heart- protection benefit, that doesn't mean women should take the drugs solely to boost their heart health. "We're certainly not trying to get everyone back on hormone therapy," says Dr. Manson, who has no financial ties to hormone makers. "But this finding should be reassuring to younger women considering hormone therapy to treat menopause symptoms."

The new analysis also raises questions about whether hormone makers will seek labeling changes from the Food and Drug Administration. After the initial scare, the FDA required estrogen products to carry a warning that the drugs may increase risk for heart attack, based on the health initiative's results. But the latest analysis shows the drugs don't increase heart-attack risk for the vast majority of women who use the drugs.

A spokesman for Wyeth, maker of Premarin, the estrogen drug studied in the health initiative, said the company will study the data and decide whether to seek labeling changes. Calls to the FDA weren't returned.

The warnings on hormone products are confusing to women, says Lila E. Nachtigal, a professor at New York University. "From the clinician's point of view, we wish the FDA would re-evaluate some of the wording on the package insert," says Dr. Nachtigal.

Wall Street Journal. (Eastern edition). New York, N.Y.: Feb 14, 2006. pg. D.6

Scientists have re-engineered a well-known antibiotic to counter drug resistance forming a new molecule in the process that could assist in treating hospital infections, which were previously resistant to common antibiotics putting its use under the spotlight.

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