Regulator orders drug companies to study suicide risk during trials

Andrew von Eschenbach, U.S. Food & Drug Administration commissioner, speaks to the media during a news conference in Hyderabad, India. (Racha Ramesh/Bloomberg News)

Regulator orders drug companies to study suicide risk during trials

After decades of inattention to the possible psychiatric side effects of experimental medicines, the U.S. Food and Drug Administration is requiring drug makers to study closely whether patients become suicidal during clinical trials.

The new rules represent one of the most profound changes of the past 16 years in regulations governing drug development in the United States. But since the regulator's oversight of experimental medicines is done in secret, the agency's shift has not been announced publicly.

The drug industry, however, is keenly aware of the change. For the first time, the agency is asking makers of drugs dealing with obesity, urinary incontinence, epilepsy, smoking cessation, depression and many other conditions to put comprehensive suicide assessments into their clinical trials.

In recent months, the agency has sent letters - it would not say how many - to drug makers requiring that they use such a scale. Merck, Sanofi-Aventis and Eli Lilly are all using a detailed suicide assessment in clinical trials being conducted now.

The seeds for the new U.S. effort were planted four years ago with the discovery that antidepressants might cause some children and teenagers to become suicidal. Top agency officials at first discounted the finding but commissioned researchers from the Columbia University department of psychiatry, led by Kelly Posner, to reanalyze the drugs' clinical trials. This work led the drug agency and its experts to view the risk as real.

Then it received an application for rimonabant, a much-heralded obesity drug developed by Sanofi-Aventis, the French drug giant. As agency medical reviewers pored over the drug's clinical trial data, they discovered hints that it could cause psychiatric problems, too.

Unsettled by their experience with antidepressants, agency reviewers again ordered the use of Posner's system. The assessment found that the drug doubled the risk of suicidal symptoms. In June, an agency advisory committee voted unanimously that the regulator reject rimonabant because of its psychiatric effects, and Sanofi-Aventis withdrew the application, although the drug is sold in Europe.

Just this month, published results of a trial of Merck's obesity drug taranabant showed similar psychiatric problems.

Fears have grown that drugs used to treat epilepsy, seizures and mood disorders may have similar effects. Examination of these medicines by the agency should be completed this year.

Suddenly, agency officials realized that multiple classes of medicines might cause dangerous psychiatric problems.

"Clearly we were somewhat surprised when this signal emerged in the pediatric antidepressant data," said Dr. Thomas Laughren, the drug agency's director of the division of psychiatry products. "So various groups within FDA are now looking at suicidality more broadly as a possible adverse event."

When Fire Strikes, Stop, Drop and... Sing?

When Fire Strikes, Stop, Drop and... Sing?

For over 150 years, scientists have known that fires can be extinguished with sound waves, but they still don't know how 

 
FIRE SILENCE: Sound can extinguish flame as this video proves, but scientists still are not sure how.

"I throw more power into my voice, and now the flame is extinguished," wrote Irish scientist John Tyndall about his experiments with sound and fire in 1857. Countless public demonstrations and a handful of lab tests later, researchers are still struggling to determine exactly how sound snuffs flames.

Sound travels in waves, which are simply variations of pressure in a medium—whether solid, liquid or gas. The energy from vibrating objects, such as speaker membranes, moves from particle to particle in the air in a repeating pattern of high- and low-pressure zones that we perceive as sound. According to the ideal gas law, temperature, pressure and volume are related; therefore, a decrease in pressure can lead to a corresponding decrease in temperature, which may explain how sound can extinguish a flame.

In 2004 Dmitriy Plaks and several of his fellow students at the University of West Georgia tested whether sound waves can douse fires in hopes of using sound to extinguish flames in a spacecraft. VIDEO They placed a candle in a large topless chamber with three bass speakers attached to the walls. The candle was lit and the Canadian rock band Nickelback's "How you remind me" was pumped through the subwoofers. Within roughly 10 seconds, once the song hit a low note, the flame was out, according to results published in 2005 in The Journal of the Acoustical Society of America.

"We don't know exactly what's going on," Plaks says, now a student at the Georgia Institute of Technology.

Physicist James Espinosa at Rhodes College in Memphis, Tenn., a former advisor to the student team, notes that the candle wasn't running out of oxygen to fuel the flame because the chamber was large and open to the air. He also doesn't believe that wind—which would actually displace the warm air around the candle with cooler air—had put out the fire, although only high-resolution thermal images would have been able to verify that.

There is another indication that the fire hadn't been extinguished by wind: frequency (the time it takes for succeeding peaks of a sound wave to pass a fixed point). "There's some special frequency at which a candle flame extinguishes," Espinosa notes. The students tested a range of frequencies from five to several hundred hertz. They found that the effective range was between 40 and 50 hertz, within the range of human hearing.

Plaks speculates that the pressure drop created by the sound wave was what extinguished the flame. Gary Ruff, project manager for fire suppression technologies at NASA's Glenn Research Center in Cleveland, agrees: if the difference between the high-pressure peak and low-pressure trough in the sound wave was large enough, the flame would go out.

Such acoustic fire suppression might prove useful in space, Espinosa suggests. "Not having to use water or toxic gas is a huge benefit" for spaceships, he says. But Ruff and NASA disagree with him: Generating the sound waves to extinguish a fire would require electricity, and astronauts would also have to be able to see the flames in order to direct sound waves at them. "[We are] looking for a very reliable, stand-alone system," Ruff says, such as chemical extinguishers.

Nevertheless, next summer Espinosa will try to extinguish a larger flame with a smaller speaker system. Instead of using the vibrating membrane of a subwoofer, he plans to create an electric arc (current that travels through the air between two electrodes), like that used for welding. This spark creates a shock wave that can be focused with an acoustic horn so that an array of such waves can be aimed at the fire.

Such a system might prove useful here on Earth for putting out fires in locations whose contents could be water-damaged by sprinkler systems, Espinosa says, such as museums that house valuable artwork or centers with data servers or other electrical equipment. "Sound is being used to cut pieces of metal, to destroy kidney stones," he adds. "It can do more than people give it credit for," including, apparently, firefighting.

Using Ion Beams to Catch a Thief (and Other Perps)

Using Ion Beams to Catch a Thief (and Other Perps)

U.K. researchers test a way to examine crime scene evidence at the atomic level 

 
HEAVY ANALYSIS: Don't expect investigators to bring ion beam analysis equipment to the crime scene. Researchers at the University of Surrey's Ion Beam Center require large machinery to carry out their experimentation using ion beams to detect trace elements contained within crime scene evidence.

The ease with which TV's intrepid crime scene investigators employ science to analyze evidence and catch the perps belies the reality of most criminal investigations. Although fingerprints, gunshot residue and other forensic evidence is critically important in connecting a suspect to a crime, the very methods used to analyze such samples often corrupt or destroy them.

In an attempt to spare delicate evidence, researchers at the University of Surrey in England are experimenting with a technique that uses ion beams to detect trace elements contained within particles found on a suspect's body or clothing without contaminating or ruining the evidence.

"Forensics is a really interesting discipline and something [an] ion beam is suited for," says Melanie Webb, a fellow at the university's Ion Beam Center who is leading its forensic analysis research. "You can see which elements you have, even trace elements. At a forensics level, residues and soils are usually studied using electronic microscopy, which has a lower level of sensitivity than [an] ion beam."

Ion-beam analysis allows investigators to compare the evidence found at a crime scene with evidence found on a suspect—or in a suspect's home or car—at the atomic level. "If you compared two samples of gunshot residue, you would check the elemental composition of these samples to see if they match," Webb says. "Ultimately, the advantage of the technique from a forensic point of view is that it's not destructive." Investigators do not have to use any chemicals on a sample to prepare it for analysis, which means the same evidence can be preserved and studied multiple times.

Ion-beam analysis was first discovered about a century ago after Lord Ernest Rutherford's experiment with backscattering spectroscopy, which measures the number and energy of ions backscattered from atoms in the sample being tested. In addition to the Rutherford backscattering (RBS) spectrometry approach, other ion-beam techniques include particle-induced X-ray emission (PIXE), during which X-rays are emitted that are characteristic of the elements in the sample, and secondary ion mass spectrometry (SIMS), a process that uses a low-energy ion beam directed at atoms in a sample's outermost layer. In SIMS, these secondary ions are then analyzed in a mass spectrometer.

In many police investigations, soil samples are compared in an effort to link a suspect to a specific location. "Many soils in the U.K. contain a mixture of commonly occurring minerals (such as quartz, calcite, feldspar, biotite) and, therefore, mineralogy studies can fail to uniquely distinguish soils from different locations," Webb said last week during a presentation to The Royal Society—the U.K.'s national academy of science—describing how ion-beam technology could be used to aid law enforcement. "The high sensitivity of ion-beam techniques to trace elements can establish similarities or differences between the samples to a greater degree of certainty than conventional methods."

Other clues, such as fingerprints, have likewise been limited by traditional analysis, which takes into account the shape and spacing of the ridges on a suspect's fingers. In many cases, the fingerprint may be incomplete or too faint to resolve, Webb says. Many fingerprint tests also rely on chemical interactions between a developer and the proteins, fats or amino acids found in a print, but these interactions vary depending upon the chemical composition of the surface—glass, wood, etcetera—from which the prints are lifted. Recent studies have demonstrated that ion beams can be used regardless of the surface to provide additional chemical information by picking up traces of drugs, gunshot residue and other incriminating evidence.

Webb says she is working with the Surrey police department on a "very high profile case involving this type of study, in which it is hoped that PIXE will help to solve the case." Neither she nor a police spokesperson would identify the case.

Late last year, Surrey police and university officials began meeting to discuss ways in which ionic beam analysis might be used for law enforcement. Webb's research "may offer exciting opportunities for the future," says Martin Hanly, the department's acting scientific support manager.

Hanly also makes clear that, even though Webb's work is worth exploring, this does not mean that current investigative techniques and technologies are lacking. "To find evidence, you may use techniques such as looking for evidence with the naked eye, high-intensity light sources, chemicals, tapings, powders and many others," he says, adding that a crime scene examiner may recover fingerprints, glass, tool marks, DNA swabs, blood, footprints, fibers and other exhibits from a crime scene that each require separate analysis, techniques and skills. "There are many techniques for recovery of many types of forensic evidence," he notes.

Still, Webb's work represents a possible advance in the field of forensics, which "is constantly evolving," Hanly says. It is impossible to say yet whether ion-beam analysis will significantly take a bite out of crime, because it has yet to be used in many real-life investigations. But researchers hope the nascent technology will prove itself a useful law enforcement tool, one day becoming a routine part of criminal investigations.

A Positioning System That Goes Where GPS Can't

A Positioning System That Goes Where GPS Can't

Indoor positioning system technology uses radio, ultrasound or infrared signals to more precisely track locations where GPS signals are blocked

 
SUPER SONIC: Sonitor's tags emit ultrasound waves that the indoor positioning system can use to identify wearers.

 
WHERE ARE YOU?: When ultrasound signals—which have short wavelengths—are emitted, the walls and doors confine the signals to that room. Sonitor is trying to improve the accuracy of its ultrasound system by shaping the sensitivity of its detectors to create "subzones."

Global positioning system (GPS) technology—now found in everything from cars to wristwatches—has become increasingly popular over the past few years for tracking location. But it has its limits—most notably, roofs, walls and floors that shield satellite signals and keep them from locating GPS receivers indoors.

Enter the indoor positioning system (IPS), a budding technology that IPS manufacturers envision as one day tracking the movement of firefighters battling blazes inside burning buildings, patients in hospitals and even retail merchandise swiped from store shelves. Although this has sparked invasion-of-privacy fears in some, the technology itself is designed to deliver useful locator services that pick up where GPS leaves off.

Why can IPS go where GPS cannot? GPS technology relies on signals from multiple satellites and employs a triangulation process to determine physical locations with an accuracy of about 33 feet (10 meters); the most common forms of IPS, both in use and under development, employ radio, ultrasound or infrared signals to home in on enclosed locations.

Radio signal–based systems that rely on wireless local area networks (WLANs) and Wi-Fi signals have several advantages over indoor positioning systems designed to rely on ultrasound or infrared, one former IBM researcher says. "The biggest advantage for wireless LANs is [that] the technology is relatively cheap and available in a lot of places," says Jin Chen, a PhD student researching distributed systems and autonomic computing at the University of Toronto, who in 2003 as a researcher with IBM in China co-wrote a paper that examined the use of WLANs for indoor positioning systems.

Many businesses and homes already have wireless networks for connecting laptops, PDAs and mobile phones, and these devices could be tracked simply by adding enabling software, Chen says. WLAN-based systems also cover larger areas than other types of indoor positioning systems and could even work across multiple buildings.

Companies that make ultrasound-based IPS say that sound waves can more accurately pinpoint people and objects than radio-frequency waves, which can be picked up by multiple sensors, making it difficult to figure out the exact proximity of a particular object to a given sensor. "If you have an RF [radio-frequency] tag, it is emitting radiation through its antenna," says Wilfred Booij, chief technology officer of Sonitor Technologies, AS, based in Oslo, Norway. The accuracy of RF waves is diminished within buildings, where the waves reflect off of metallic or ceramic objects. "If you have a very open area, you can have very good accuracy with RF—between five and 10 meters [16 and 33 feet]," he says. "But in complex buildings like a hospital, accuracy is more like 15 meters [49 feet]."

Ultrasound is detected by microphones placed in rooms where the tracking is to be done. When ultrasound signals—which have short wavelengths—are emitted, the walls and doors confine the signals to that room. Sonitor is trying to improve the accuracy of its ultrasound system by shaping the sensitivity of its detectors to create "subzones."

"With ultrasound, we have much better control over signal strength," Booij says. "A microphone can be designed to be more sensitive in a particular direction. We can shape the sensitivity of our detectors so that rather than picking up all the signals in a room, they pick up a specific signal that can be specific to a particular doctor or patient."

Sonitor so far has installed its technology in 20 hospitals in the U.S. and Europe, where physicians and staff use the ultrasound systems to track patients and medical equipment. Among them, the University of Pittsburgh Medical Center (U.P.M.C.) since October has been testing different IPS technologies to create a "smart room" that detects a doctor or nurse who has entered it and displays patient information on bedside monitors.

U.P.M.C. is using Sonitor technology to identify to patients the different doctors, nurses and staff they encounter during their stays. The goal is to help patients keep track of their caregivers, something not easy to do if the patients require round-the-clock care from multiple doctors working different shifts. Each worker wears a tag smaller than a pager that emits a sound the IPS can detect when he or she enters a smart room. An ultrasound detector there reads the tag and identifies the staffer by name and job title, displaying the information on a flat-screen monitor at the foot of the patient's bed.

In this pilot phase, tags have been assigned to doctors, nurses, nursing assistants and phlebotomists as well as dietary hosts and hostesses. With about 5,000 physicians affiliated with U.P.M.C., including more than 2,300 staff physicians, IPS is expected to introduce efficiency, accuracy and familiarity in an environment where patients are often ill-informed and overworked doctors are prone to make mistakes.

Acoustic guitar subtleties re-created by DSP

Acoustic guitar subtleties re-created by DSP

Guitarists usually associate digital signal processing with electric, rather than acoustic, guitars, especially after early attempts to apply DSPs to acoustic instruments led to modeling effects that kept the guitars from performing as advertised. Now Fishman Transducers Inc. says it has repurposed the Analog Devices Inc. Blackfin DSP to perform "digital acoustic imaging" instead of modeling, making acoustic guitars with an inexpensive piezoelectric pickup sound as if they were in a pristine studio in front of an expensive condenser microphone. "When we first considered digital signal processing for guitars, we were just thinking modeling--making a Gibson sound like a Fender," said Larry Fishman, president of Fishman Transducers (Wilmington, Mass.). "We tried that, but found that it's much too complicated a problem, with all the subtle complexities. Now what we do instead is make an acoustic guitar sound as good in your home recordings, or live onstage, as it does in a professional studio." The idea, he said, "is to capture that great studio sound and bring it out to real world of performances." Fishman's digital acoustic imaging algorithm works by comparing the sound of a guitar under perfect conditions—in an ultraquiet studio with a variety of expensive condenser microphones placed at various distances in front of it—with the signal you get from a piezoelectric transducer or pickup, which Fishman places under the bridge saddle. The transducer senses the originating excitation of the strings, but is not sensitive to the sound hole resonances. And it doesn't hear the mix of phases in front of the instrument as various frequencies radiate differently off the top, sides and head of the guitar. Fishman says it can capture and re-create all these subtle frequency and phase differences by running its algorithm on a Blackfin DSP from Analog Devices (Norwood, Mass.), contouring the audio from the raw transducer so that it sounds as if were in the studio. "First, we take a guitar into the studio and do a two-channel recording—one channel records from what the transducer hears and the other channel records what the microphone hears," said Fishman. "Then we run the algorithm we developed to make a very close comparison of the two signals in the frequency domain, subtract one from the other to get their difference, then convolve the two to get what we call a sound image." From the sound image, Fishman Transducers creates a custom filter with more than 2,000 frequency taps for the Blackfin DSP. "We not only adjust the amplitude of each frequency, but also make critical-phase adjustments, which is where the magic comes in," Fishman said. "Without that phase information, we would just have a 2,000-band graphic equalizer. But by adjusting the phase information too, we get three-dimensionality in the sound."   As a result, he said, "when we make a filter from our acoustic image and download it into the Blackfin, then drive that image with the raw guitar signal from the transducer, it is transformed into what the microphone would be hearing in a professional studio." In practice, Fishman records each instrument with a half-dozen well-known studio-recording microphones, then offers those sounds as selections to the guitar user. Musicians who add Fishman's Aura preamp to their own guitar, as opposed to buying a guitar with a built-in Fishman preamp, can download as many as 16 acoustic images from a Fishman Web site. The site already offers more than 1,000 acoustic images for nearly every acoustic guitar in existence. "We have a continuous flow of instruments coming into our shop from around the world, and we update our list with new acoustic images weekly," said Fishman. Users can select acoustic images by guitar body type, wood, microphone type and distance between microphone and instrument. "You don't need an exact match always, and there are some surprising combinations that just happen to sound good," Fishman said. For serious guitarists, the company will create a custom acoustic image for $250. Musicians ship their guitars to Fishman's studio to get a professionally calibrated acoustic image they can load into their Aura preamp. "This really lets your guitar shine, especially onstage or in home recording situations, where you don't have a pristinely quiet recording environment or a closet with $250,000 worth of fancy microphones," Fishman said. A major portion of Fishman Transducers' business is from guitar manufacturers that include a built-in Fishman pickup and preamp inside their acoustic guitars. Guitar makers send finished instruments to Fishman, which calibrates an acoustic image for that particular type of guitar and supplies a custom pickup and preamp to re-create the plush studio sound at the push of a button. To meet the long-battery-lifetime requirements of in-guitar preamps, Fishman says the company evaluated the available DSPs with energy efficiency as the No. 1 concern. "We ran a competitive evaluation of all the other DSPs, and Blackfin was the clear choice for us, because its greater power efficiency gives us a much longer battery life than we could get with any other commercial DSP processor," said Fishman. To get that longer battery life, Fishman runs the Blackfin processor at an energy-saving 169 MHz with a supply voltage of just 0.8 V. "Equally important is that we don't need a separate microcontroller for the user interface," said Fishman. "Previous to Blackfin, we had to use a separate microcontroller to read the knobs and handle the user interface, but it was power-hungry and needed a different supply voltage from the DSP." At the recent National Association of Music Merchants trade show, Fishman showed a new line of acoustic-effects pedals--reverb, delay and chorus--that use the same printed-circuit board as Aura, but program the Blackfin DSP to perform these more-traditional guitar effects.