Louis J Sheehan Esquire 30026

Sweeping Overview Suggests Suppression of Negative Data
Has Distorted View of Drugs
By DAVID ARMSTRONG and KEITH J. WINSTEIN
January 17, 2008

The effectiveness of 12 popular antidepressants has been exaggerated by manufacturers' selective publication of favorable results, researchers asserted in a new review of unpublished data that were submitted to the Food and Drug Administration.

As a result, the review concludes, doctors and patients are getting a distorted view of the effectiveness of blockbuster antidepressants like Wyeth's Effexor and Pfizer Inc.'s Zoloft. The review was published in the New England Journal of Medicine.
ACCENTUATE THE POSITIVE

A review of research submitted to the FDA:
• Of 74 studies reviewed, 38 were judged to be positive by the FDA. All but one were published, researchers said.
• Most of the studies found to have negative or questionable results were not published, researchers found.
Source: The New England Journal of Medicine

Since the overwhelming amount of published data on the drugs show they are effective, doctors unaware of the unpublished data are making inappropriate prescribing decisions that aren't in the best interest of their patients, according to researchers led by Erick Turner, a psychiatrist at Oregon Health & Science University. Sales of antidepressants total about $21 billion a year, according to IMS Health.
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Wyeth and Pfizer declined to comment on the study results. Both companies said they had committed to disclose all study results, although not necessarily in medical journals. GlaxoSmithKline PLC, maker of Wellbutrin and Paxil, said it has posted the results of more than 3,000 trials involving 82 medications on its Web site, and also has filed information on 1,060 continuing trials at a federal government Web site.

Schering-Plough Corp., whose Organon Corp. unit markets Remeron, and Eli Lilly & Co., which makes Prozac, said their study results were indeed published -- not individually, but as part of larger medical articles that combined data from more than one study at a time. The New England Journal study counted a clinical trial as published only if it was the sole subject of an article. "Lilly has a policy that we disclose and publish all the results from our clinical trials, regardless of the outcomes from them," a Lilly spokeswoman said.

Pharmaceutical companies are under no obligation to publish the studies they sponsor and submit to the FDA, nor are the researchers they hire to do the work. The researchers publishing in the New England Journal were able to identify unpublished studies by obtaining and comparing documents filed by the companies with the FDA against databases of medical publications.

"There is no effort on the part of the FDA to withhold or to not post drug review documents," an FDA representative said. For newer drugs, information is posted online "as soon as possible." Older documents aren't always available online and efforts to add those files to the Web are slowed by "a lack of resources," the agency said, acknowledging that there is a backlog in complying with records requests.

A total of 74 studies involving a dozen antidepressants and 12,564 patients were registered with the FDA from 1987 through 2004. The FDA considered 38 of the studies to be positive. All but one of those studies was published, the researchers said.
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The other 36 were found to have negative or questionable results by the FDA. Most of those studies -- 22 out of 36 -- weren't published, the researchers found. Of the 14 that were published, the researchers said at least 11 of those studies mischaracterized the results and presented a negative study as positive.

Five Trials

For example, Pfizer submitted five trials on its drug Zoloft to the FDA, the study says. The drug seemed to work better than the placebo in two of them. In three other trials, the placebo did just as well at reducing indications of depression. Only the two favorable trials were published, researchers found, and Pfizer discusses only the positive results in Zoloft's literature for doctors.

One way of turning the study results upside down is to ignore a negative finding for the "primary outcome" -- the main question the study was designed to answer -- and highlight a positive secondary outcome. In nine of the negative studies that were published, the authors simply omitted any mention of the primary outcome, the researchers said.

The resulting publication bias threatens to skew the medical professional's understanding of how effective a drug is for a particular condition, the researchers say. This is particularly significant as the growing movement toward "evidence-based medicine" depends on analysis of published studies to make treatment decisions.

Colleagues' Questions

Dr. Turner, who once worked at the FDA reviewing data on psychotropic drugs, said the idea for the study was triggered in part by colleagues who questioned the need for further clinical drug trials looking at the effectiveness of antidepressants.
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"There is a view that these drugs are effective all the time," he said. "I would say they only work 40% to 50% of the time," based on his reviews of the research at the FDA, "and they would say, 'What are you talking about? I have never seen a negative study.'" Dr. Turner, said he knew from his time with the agency that there were negative studies that hadn't been published.

The suppression of negative studies isn't a new concern. The tobacco industry was accused of sitting on research that showed nicotine was addictive, for instance. The issue has come up before notably with antidepressants: In 2004, the New York state attorney general sued GlaxoSmithKline for alleged fraud, saying it suppressed studies showing that the antidepressant Paxil was no better than a placebo in treating depression in children. Glaxo denied the charge and eventually settled with the attorney general. The company later posted on its Web site the full reports of all of the studies of Paxil in children.

But publication of negative studies is an issue that cuts across all medical specialties. And it has engendered some strong reactions in the medical-research world: To make it harder to conceal negative study findings, an association of medical journal editors began requiring in 2005 that clinical trials be publicly disclosed at the outset to be considered for publication later. The system isn't foolproof, since manufacturers often run exploratory studies without registering them and can selectively disclose favorable results. The rule only applies to studies intended for publication in a medical journal.

Some studies that don't eventually get published are registered with online trial registries, including the federal government's www.clinicaltrials.gov. Nonetheless, many studies still aren't being registered or reported, says Kay Dickersin, the director of the Center for Clinical Trials at the Johns Hopkins Bloomberg School of Public Health. "We need something more meaningful," she said. "The average person has no idea that www.clinicaltrials.gov is not comprehensive."

The New England Journal study also points to the need for the FDA to disclose more information about the studies it receives, says Robert Hedaya, a professor of clinical psychiatry at Georgetown University Hospital. He said it was "disturbing" that the information on the negative studies wasn't made widely available by the FDA.
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The FDA does post information, including unpublished studies, for some drugs on its Web site, says Dr. Turner. But information that hasn't yet made it online is hard to come by. Dr. Turner said he made public records requests for information not on the Web site more than a year ago, but the requests have gone largely unfulfilled. He said he was able to get some of the FDA's information on unpublished studies from other researchers who acquired it from the agency through their own record requests.

The 'Effect Size'

In this week's study, the researchers found that failing to publish negative findings inflated the reported effectiveness of all 12 of the antidepressants studied, which were approved between 1987 and 2004. The researchers used a measurement called effect size. The larger the effect size, the greater the impact of a treatment.

The average effect size of the antidepressant Zoloft rose 64% by the failure to publish negative or questionable data on the drug, the researchers found.



Parents' Pessimism Affects Children's Investing
Parental attitudes can significantly influence children's decisions to invest. The key is the extent to which parents trust society, according to "Social Capital as Good Culture," a new National Bureau of Economic Research working paper by Luigi Guiso of the European University Institute; Paola Sapienza of the Kellogg School of Management and Luigi Zingales of the University of Chicago.

The economists find that pessimism among parents is passed on to their children as a form of social capital, which is defined as the set of beliefs and values that inspire cooperation in members of a community. Passing on pessimism leads children to avoid investment and prevents them from gaining their own knowledge of society, according to the paper. Allowing pessimistic values to flow from generation to generation until society is stuck at a point the paper deems a "no-trust no-trade equilibrium."

They tested their model using two different samples: the World Value, a survey to determine the correlation between young people's rate of learning and average level of trust in their parents, and the German Socio Economic Panel to link parents' and children's beliefs.

While it doesn't specify how to alter a low trust state, it shows that even a temporary shock to society can alter the perceptions passed from one generation to the next. In a shock that lasts three generations, for example, 19% of families eventually stop investing. If the shock lasts five generations, it drops to 8%.

"This 'temporary' shock is sufficient to induce almost all family lines to have an optimistic prior and always invest. Most interesting, this effect persists forever even after the shock disappears," the researchers conclude.
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The economists sought to prove that lasting effect by demonstrating that the difference in social capital in Northern and Southern Italy today resulted from a period of independence in cities in Northern Italy more than 500 years ago. Italian literature from the 19th century showed that Northern literature was punctuated by intense optimism and faith in others, while Southern literature displayed a sense of mistrust toward the community. Data from the 1990s shows the sentiments persisted long after the "shock." Though 42% of Northerners trusted others, only 25% of Southerners felt the same.

The cycle can change within individuals as well, though. The paper found that as a person ages, trust tends to increase as his life experiences meld with his parents' views. This was based on the finding that parents generally pass conservative versions of their beliefs on to children. It also found that mothers have a stronger influence in passing on personal values and beliefs.

Shifting levels of trust are applicable to second generation Americans also, who often correlate their trust in American society with the level they held in their native countries. This can continue for generations.

"Our model implies also that when transmitting priors, parents should do so in a conservative way, so that the prior they transmit is on average lower than the one they hold," the researchers conclude. "Furthermore, parents that have stronger beliefs about the trustworthiness of others should transmit less conservative priors." -Sara Murray






Telescopes have captured astonishing images of far-away galaxies and other cosmic mysteries. Now, a new book called Touch the Invisible Sky is helping everyone appreciate those pictures, even people who can't see.

This isn't the first book written by Noreen Grice, an astronomer who works at the Museum of Science in Boston. Back in 1984, Grice was a 21-year-old studying astronomy at Boston University. She had a job at the planetarium, and one Saturday, a group of blind people came to the show.

"I didn't know what to do because I didn't know anyone who was blind," says Grice. Her manager told her to just help the people to their seats.

After the show was over, Grice went up to the group.

"I said, 'So how did you like the show?' And there was an uncomfortable pause," she recalls. "And then they said, 'This stunk' and walked away. And that left me speechless because I thought the planetarium was, like, the best place in the world."

The next day, Grice took a bus to a nearby school for the blind. She found its library and looked for astronomy books. They were thick books, printed in Braille.

"But something was missing. I said, 'Where are the pictures? Are there any pictures these books?'"

The librarian explained that it's expensive to translate an image into raised lines and textures that a person can feel with their fingers. So textured images are uncommon in books for the blind. Grice hated the idea that blind people weren't getting the same kind of cool astronomy books she loved as a kid.

"I had grown up in the housing projects outside Boston," says Grice. "People would say, 'you're a project kid, you're not welcome here.' I understood what it meant to be labeled. And I didn't really know how to make astronomy accessible. But I thought, 'I'll try.'"

Her first book, Touch the Stars, came out in 1990. She used a Braille printer to trace out the constellations. Her next book, Touch the Universe, traced out photos taken by the Hubble Space Telescope. Grice created that one using thin plastic sheets.

"Basically, I was etching them by hand, in my kitchen," she says. "Some were like, really difficult. When you have diffuse gas, that you can hardly see, it is very difficult to apply a texture to it."

Touch the Invisible Sky, her latest book, was written with two co-authors. It's beautiful, designed to be read by both blind people and sighted people.

The book has images taken by telescopes that detect things like radio waves, x-rays and gamma rays — the wavelengths of light that no one can see with the naked eye.

"I think we all have the same thing in common with this book," says Grice. "No human can see these other wavelengths so we're all approaching it together."

There's a real need for more books like this one, says Marc Maurer, president of the National Federation of the Blind.

"Most people think that astronomy is the study of light, and they think therefore that blind people can't do it and would not be interested," he says. "Blind people can do it, and we find it fascinating."

Maurer loved the science textbooks his mom read to him when he was going to school. But a popular science book he could read by himself — there was nothing like that.

"There still are not enough books," he says, explaining that exciting science books with pictures and graphics are a rarity for blind people.

That's one reason why Chelsea Cook, a high school student in Newport News, Virginia, got her family to drive four hours to Baltimore for the new book's unveiling. She says Noreen Grice's astronomy books are "really interesting, you know, the visuals are easy to read, and they're just cool to look at."

Cook says she has enough vision to see a full moon, but not stars. Still, she wants to study astrochemistry and astrophysics. And she's fascinated by the idea of space exploration.

Her ultimate career goal? To become the first "blind astronaut." It will be "a lot to work towards," she says, "but I think it's possible."








The United States Constitution never uses the word "God" or makes mention of any religion, drawing its sole authority from "We the People." However, Republican presidential candidate Mike Huckabee thinks it's time to put an end to that.

"I have opponents in this race who do not want to change the Constitution," Huckabee told a Michigan audience on Monday. "But I believe it's a lot easier to change the Constitution than it would be to change the word of the living god. And that's what we need to do -- to amend the Constitution so it's in God's standards rather than try to change God's standards so it lines up with some contemporary view."

When Willie Geist reported Huckabee's opinion on MSNBC's Morning Joe, co-host Mika Brzezinski was almost speechless, and even Joe Scarborough couldn't immediately find much to say beyond calling it "interesting,"

Scarborough finally suggested that while he believes "evangelicals should be able to talk politics ... some might find that statement very troubling, that we're going to change the Constitution to be in line with the Bible. And that's all I'm going to say."

Geist further noted of Huckabee that if "someone without his charm," said that, "he'd be dismissed as a crackpot, but he's Mike Huckabee and he's bascially the front-runner."
















PORTALS
By LEE GOMES



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If You're Not Insane
About Sound, Maybe
You Can Just Go Crazy
January 16, 2008; Page B1

If you had to choose between two sets of speaker cables, one costing a few dollars and sounding fine, the other a few thousand dollars but perhaps sounding slightly better, and you chose the second pair, then you would have had a great time last week in Las Vegas.

The city's many goings-on included The Home Entertainment Show, an audiophile trade show held in two small motels off the Strip. Audiophiles, as you probably know, are the hi-fi zealots who think nothing of spending $50,000 on a turntable. I've learned over the years that audiophiles actually come in two varieties: the totally insane and the merely crazy.

The latter have a sense of humor and shrug that theirs is just one of many hobbies -- like wine -- for people with money, expansive vocabularies and the ability to discern differences lost on the rest of us.

By contrast, my interests involve the extent to which beliefs influence perceptions. Scientists have discovered that brain scans of wine drinkers show they physically enjoy a wine more if they think it is expensive. Can audiophiles really hear all the differences they say they can, without being influenced by the brand or price of their equipment?

To find out, Portals became an official exhibitor at T.H.E. Show last week. I set up a room with two sound systems, identical except for one component. Everything except the speakers was hidden behind screens. (A shout-out to Totem Acoustics for the Forest speakers loan and to Magnum Dynalab for the MD-308 amps. They all sounded sensational.)

With the same music playing on both, participants used a remote control to switch between the two, and then tell me which sounded better.

One of the tests compared a high-quality MP3 file from an iPod with a CD on a $3,000 player. Three-quarters of the 24 people taking this test preferred the CD.

That was no surprise. However, when I played .wav files on the iPod -- these are digital but uncompressed files; I was connecting the headphone jack to the amplifier -- 52% of the 21 who took this test preferred the iPod.

That made me smile, not because snooty audiophiles got the "wrong" answer, but because it suggests great sound can come from popular, cheap gear.

I also tested speaker cables, which are controversial even among audiophiles. Some spend tens of thousands of dollars on cabling, while others consider it an absurd waste of money.

Using two identical CD players, I tested a $2,000, eight-foot pair of Sigma Retro Gold cables from Monster Cable, which are as thick as your thumb, against 14-gauge, hardware-store speaker cable. Many audiophiles say they are equally good. I couldn't hear a difference and was a wee bit suspicious that anyone else could. But of the 39 people who took this test, 61% said they preferred the expensive cable.

That may not be much of a margin for two products with such drastically different prices, but I was struck by how the best-informed people at the show -- like John Atkinson and Michael Fremer of Stereophile Magazine -- easily picked the expensive cable.

Its sound was described as "richer," "crisper" and "more coherent." Like some wines, come to think of it.

In absolute terms, though, the differences weren't great. Mr. Atkinson guesstimated the expensive cables sounded roughly 5% better. Remember, by definition, an audiophile is one who will bear any burden, pay any price, to get even a tiny improvement in sound.

Attendance at the show was disappointing, so I didn't get the numbers of participants I wanted. Even if I had, I'm not sure I would have settled anything. These "A-B" tests have limits, including the fact that differences you might not pick up right away can become more apparent with extended listening.

Skeptics out there might think I've gone all mushy and credulous on them.

Not so.

Consider the thriving audiophile product category of power-line conditioners, said to remove noise and distortions caused by your electrical supply, a problem you may not realize you have. A rep from Audience LLC accepted my invitation for an A-B test of the company's $2,800 AdeptResponse aR6 conditioner.

He picked the system using his conditioner -- the other was plugged into the wall -- two out of three times.

Note that the aforementioned "merely crazy" audiophiles say that while they might have home setups costing six figures, the rest of us can get splendid sound for under $1,000 by shopping at specialty audio shops, the sort that sell unfamiliar brands.

I can't help you with brands, but my tests suggest you might want to do your ripping as .wav files. While they take up a lot more room than MP3s, falling disk prices make this feasible even for big collections.

As for cables, good ones can cost well under $2,000. I'd still be happy at the hardware store, but you may be the golden-ear sort who can hear a difference. As in "Dirty Harry," you've got to ask yourself, "Do I feel lucky?"

Well, do you?
Cocaine Boom in Europe
Fuels New Laundering Tactics
Dirty Euros Enter U.S.
Via Latin America;
The African Connection
By MARK SCHOOFS and PAULO PRADA
January 16, 2008; Page A1

A cocaine boom in Europe and the continent's strong currency have combined to fuel a thriving industry: euro laundering.

With the euro approaching $1.50 and soaring demand for cocaine in countries like Spain and Italy, Europe has become a far more lucrative place to do business for Latin American drug cartels than in previous years.

To obscure the origins of the funds, and escape government scrutiny in the process, the cartels use a complex system to launder their proceeds -- much of which is landing on U.S. shores.

In late March, U.S. authorities arrested a man carrying a leather duffel bag who had just landed at Los Angeles International Airport on a flight from Santiago, Chile. Inside the bag was more than $1.9 million in cash, mostly in bundles of €500 and €200 notes.
Authorities are struggling to make a dent in the booming drug trade in Europe. WSJ's Mark Schoofs tags along with Spanish police as they search for clues to the source of cocaine that keeps pouring into the country.

U.S. and Chilean law enforcement officials believe the man was at the end of a money-laundering trail that begins in Europe. Over a period of four and a half years, he and his associates flew to the U.S. from Latin America some 280 times, openly toting more than $244 million worth of euros into the country, according to documents in a case brought by federal authorities in U.S. District Court in New York.

The big bills have become so symbolic of the lush life that they have recently crept into pop culture: The rapper Jay-Z's video for Blue Magic -- the debut single from his new album "American Gangster" -- features a suitcase full of €500 notes and someone thumbing through a stack of them as Jay-Z raps the words, "the kilo business." Hype Williams, director of the music video, said that he and Jay-Z chose euros because they are "more valuable" and because they wanted to "one-up" their hip-hop competitors by showing "the things people are into now."

The wads of euros carried by people like the man arrested at LAX are often the spoils of Europe-bound cocaine shipments -- many of which transit through Africa, law-enforcement officials say.

Consumption of the drug has soared in much of Western Europe, according to a report released last year by the U.N. Office on Drugs and Crime. In Italy, use of the drug rose to 2.1% of the general population in 2005 from 1.1% just four years earlier. In France, it tripled from 2000 to 2005, from 0.2% to 0.6% of the adult population. Cocaine use in England doubled from 1998 to 2006, according to Britain's National Health Service, to 2.4% among adults.

Some narco-euros are laundered directly in Europe. But officials say the lion's share is routed back to South America as cash and eventually ends up in the U.S.

"This is still a cash business," says Donald Semesky, the Drug Enforcement Administration's head of financial-crimes investigations.

The first step is to convert small bills accumulated from thousands of street sales into €500 notes, which are easy to transport. Obtaining large quantities of these conspicuous notes, though, isn't easy. So drug traffickers turn to specialized criminal rings -- whose members are often involved in banking and real estate -- to gain access to them, says José Manuel Álvarez Luna, chief of the money-laundering section of the Spanish police.

'Bin Ladens'
[Chart]

Spain is the center for such aggregation, according to authorities. A high-level Spanish banking official says a disproportionate share of the euro zone's €500 notes, known as Bin Ladens for their scarcity, circulate in Spain.

The purpose of money-laundering is to disguise the criminal origins of ill-gotten gains so the funds appear legitimate. In most cases, laundering also helps criminals escape the notice of tax collectors and law-enforcement officials, boosting the value of their illegal proceeds.

Particularly since 9/11, tightened antilaundering regulations, known by banks as "know your customer" rules, have forced drug cartels to use more circuitous routes to circulate their funds around the globe.

For starters, the drug cartels do not themselves bring their narco-euros to the U.S. Instead, they usually sell their euros to South American black-market currency brokers or to foreign-exchange houses, known in Spanish as casas de cambio. The casas' business as currency-exchange houses gives them a natural cover for moving large amounts of cash.

But in South America, there are few if any legitimate buyers for the huge sums of euros that the casas obtain -- directly or indirectly -- from the traffickers. So the casas funnel most of the narco-euros, sometimes via middlemen, through a chain of exchange houses in countries like Colombia, Peru, Brazil and Chile, says the DEA's Mr. Semesky.

Often, the drug traffickers will sell their euros for Colombian pesos, and then the euros entering the U.S. no longer belong to the drug cartels but to the casa de cambio. In other cases, says Mr. Semesky, traffickers pay the casas to move funds into one of their U.S. bank accounts. These funds aren't usually intended for withdrawal, but rather to pay various debts. This is achieved by wiring funds to the account of whomever the trafficker wishes to pay.

On a recent night at a bar on Madrid's bustling Gran Vía, a shirtless, tattooed waiter served tables and a buxom drag queen in a nurse's uniform worked the crowd. In the trendy venue was a man in his 30s who talked by cellphone with his dealers. A few minutes later, he stepped outside, leaned into the window of a small car and handed over €60, or about $90. For that sum, he received one gram of cocaine.

Such street sales have surged. Spain now has a larger percentage of its population (3%) using cocaine than the U.S. (2.3%), the previous top per-capita consumer, according to United Nations figures. In the first half of 2007, a kilo of cocaine sold for €33,000, or about $43,900, in Madrid, more than triple the $12,500-$14,600 it fetched in Los Angeles and far more than the $13,000-$26,000 it sold for in New York, according to the Spanish police and the DEA.

Last year, seven European countries banded together to form the Maritime Analysis and Operations Center-Narcotics, or MAOC-N, an international agency dedicated to stopping drug traffic over the Atlantic. Already, the center is helping to make major busts.

In October, on the high seas off West Africa, Spanish authorities -- acting on a tip from MAOC-N -- seized an aging, cockroach-infested trawler. Called the Opnor, it allegedly had more than three metric tons of cocaine hidden below the floor of its cargo hold. Apparently registered in Panama, the vessel was captained by a grizzled Dutch man in his late 60s and is believed to have been heading toward Senegal.