Sudden Infant Death Syndrome could be caused by a problem with serotonin receptors on a specific type of neuron, according to a paper published in the March 8 

    The study provides a mechanism that could explain why infants are more likely to experience SIDS when sleeping on their stomachs, and it raises the possibility that infants at risk could ultimately be identified by a genetic test.

    The study focuses on a group of neurons called CI-pacemakers, which the study’s authors believe are responsible for gasping. The neurons have serotonin receptors on their surfaces, and when serotonin binds to the receptors it opens channels that allow a burst of calcium to flow into the neuron. This burst causes the pacemaker neurons to induce gasping.

    According to lead author Jan-Marino Ramirez, an assistant professor of organismal biology at the University of Chicago, babies who die of SIDS have an insufficient ability to gasp. When a sleeping infant is deprived of oxygen, for example because of lying on its stomach, the CI-pacemakers would normally cause the infant to gasp, and gasping would cause the baby to wake up crying, which would reset normal breathing. At this point, it might also turn over on its own or be aided by a concerned parent.

    Previous studies have shown that infants who died of SIDS had abnormal serotonin transporters, the receptor that takes serotonin into cells for recycling, Ramirez explained. The serotonin transporter is different from the serotonin receptor found on the pacemaker neurons. But because it is involved in moving serotonin into cells, it plays a role in regulating the amount of serotonin present in the body. 

    At this point, it is unclear how the disturbed serotonin transporters are linked to the pacemaker neurons that control gasping, Ramirez said. The problem with the transporters could lead to decreased levels of serotonin in the body, he said. On the other hand, he theorized, it could lead to increased levels, which, in turn, could make the body downgrade production of serotonin.

    Further research should develop the link between the pacemaker neurons and the disturbed serotonin transporters, according to Ramirez. He is also interested in learning about the connection between pacemaker neurons and the brain’s center for arousal, the locus coeruleus.

    In the clinic, it may be possible to identify babies at a high risk for SIDS by screening for disturbances in serotonin levels or serotonin transporters, Ramirez said. Looking down the road, it might be possible to identify a genetic marker that would allow physicians to associate the baby’s risk with a number. 

    It is possible that if a marker were found, babies at high risk for SIDS could be given a drug to normalize their serotonin levels, he said. But for now, Ramirez is very reluctant to use drugs that increase levels of serotonin, such as antidepressants, to correct this problem. Serotonin is a complicated molecule, which affects many systems, he explained. At this stage of understanding, it would be better to just monitor babies who are at high risk very carefully.

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A University of Chicago professor explains his findings that serotonin induces gasping in oxygen-deprived infants. These results will probably not lead to Prozac prescriptions for babies, but they could be used to find a genetic marker for SIDS risk down the road.

Sudden Infant Death Syndrome Linked to Serotonin

Drug development times decreased between 1992 and 2002, according to a study of 168 drugs in the March/April issue of 

. The paper says that time spent on R&D cannot be used to explain increasing drug prices, which have generated so much criticism in recent years. But industry experts say declining development time does not mean development costs are also going down.

    This analysis of public data from the 

 and FDA’s Web site indicates that the time spent on clinical trials for drugs approved between 1992 and 2002 did not increase. The time spent between filing a New Drug Application (NDA) and approval decreased, according to the paper.

    When organized by the year these compounds were filed as Investigational New Drugs (IND), ranging from 1985 to 1995, the total development time declined.

    This decrease in development time is consistent with data collected by the Tufts Center for the Study of Drug Development for this same period, Joseph DiMasi, the center’s director of economic analysis, said via email. But he added that data collected between 2002 and 2004 indicates that clinical development times have gotten longer in recent years. DiMasi wrote an electronic letter responding to this study on the 

    The practice of assigning certain drugs fast-track status, which began in 1998, is responsible for some of the decrease in development time, explained Salomeh Keyhani, lead author and assistant professor of health policy at Mount Sinai School of Medicine.

    “However, in our analysis we noticed that non-fast-track drugs approved after 1998 were developed more quickly than non-fast-track drugs before 1998,” Keyhani said via email. “In other words, development time has also been decreasing in spite of fast track, as well.”

    Almost every pharmaceutical company has worked to reduce development time in recent years, said Harold Glass, director of the University of the Sciences in Philadelphia’s MBA program in pharmaceutical business. Business reasons, such as maximizing the patent life of potential drugs, have driven this decline, he said.

    Decreasing development times do not necessarily mean that the costs of development are also decreasing, DiMasi added. According to Glass, development costs are going up. He cited larger patient populations and increased geographic diversity for clinical trials as reasons. In addition, he said, science of drug development has become more complex, driving costs up.

     According to Keyhani, the study shows that time spent in development does not determine drug pricing. The market sets prices for pharmaceuticals, she said. She believes that other explanations, such as development times or costs, are difficult to believe because the data supporting them is proprietary and not public.

    “You can say whatever you want, when the data is not transparent,” she said.

    Economists agree with her assessment that prices are set by how much people are willing to pay for them.

    “Economic logic tells us that R&D cost does not determine price,” DiMasi said via email. “Rather, market forces and price regulation (abroad) determine price.”

    The low-end of the price is determined by the amount of money the company needs to recover, according to Glass. The market sets the high-end of the price, he added.

    But Margaret Kyle, an assistant professor of management at Duke University’s Fuqua School of Business, explained that development costs are already spent, or “sunk,” by the time the drug reaches the market. As a result they have no relation to pricing.

    “Economic theory suggests that sunk costs should be irrelevant for pricing,” she said via email. “What matters are demand conditions and variable (production) costs.”

    Kyle added that although development time and cost do not impact pricing in her view, they could impact a company’s expectation of future profits. Expected profits decrease if the demand for the drug stays stable, but costs go up. As a result, the company might decrease its investment in developing other new treatments to account for this anticipated profit loss.

Economists discuss a recent article in Health Affairs, which argues that market demands, not R&D costs, determine drug prices.

Study Shows Development Time Decreasing

The outlook is good that Elan Corp. and Biogen Idec Inc.’s multiple sclerosis drug Tysabri (natalizumab) will return to the market after a unanimous vote last week by FDA’s Peripheral and Central Nervous System Drugs advisory committee. Industry experts are interpreting the probable return an indication that traditional risk–benefit analysis is still viable, but they also see it as a sign of the increasing importance of both the advisory committee system and data on the mechanism of drug action.

    Tysabri was taken off the market just about a year ago after it was linked with a small number of deaths from progressive multifocal leukoencephalopathy, a rare brain disease, when taken in conjunction with another MS drug, Avonex (Interferon beta-1a). The FDA is not required to follow the advisory committee’s recommendations, but it usually does. Edward Allera, head of Buchanan Ingersoll PC’s food and drug group, said comments by Robert Temple, the director of the agency's Office of Medical Policy, indicate the drug will definitely come back.

    It is still unknown what kind of restrictions the FDA would place on Tysabri, but it is likely that a patient registry will be required and possible that the drug will be indicated only for those who have already been unsuccessful with other products.

    The advisory committee’s decision reflects traditional risk–benefit analysis, said James Czaban, an attorney in Heller Ehrman LLP’s FDA group. 

    “It would be a mistake to read into this a loosening trend,” he said. “Because that’s not the way political winds are blowing.”

    According to Jill Alvarez, head of FDA regulatory practice at Nixon Peabody LLP, the advisory committee’s decision shows that for certain drugs -- those that treat serious diseases for which there are few therapeutic alternatives -- decisions about risk should be shared between the agency, the manufacturer, and patients.

    “I think it’s part of what’s starting to be a dialog on what drug approval means,” she said. “There’s a recognition that sometimes some risk sharing might be appropriate.”

    Alvarez believes risk sharing will become increasingly important as the industry moves towards personalized medicine, and that it may be appropriate for legislators to enact legal protections for drug makers in cases when, due to a lack of alternatives, patients decide to take a drug associated with a high level of risk.

    The Tysabri decision re-emphasizes the importance of deciding how risks will be determined as the industry moves towards more sophisticated drugs with narrower indications, Allera said. He noted that it could underscore the necessity of efforts like the Critical Path Initiative. It will also drive demand for including more information about a drug’s mechanism of action in future applications, he said.

    Allera noted that the Tysabri saga points out the importance of advisory committees in the approval process. The drug was initially approved without including the advisory committee step.

    “If that had been followed, it might have diffused some of the concerns,” he said. “In the future, first-in-class drugs will go through an advisory committee.”

    Czaban agreed that for first-in-class drugs, or drugs for diseases with no satisfactory alternative therapies, it “is probably best” to have an advisory committee evaluation.

The recommendation shows traditional risk-benefit analysis is still working, experts say. But they also believe the Tysabri saga illustrates a trend towards increased use of advisory committees and requirements for drug mechanism data.

Pharmaceutical Executive-03-15-2006

Sudden Infant Death Syndrome Linked to Serotonin

Study Shows Development Time Decreasing

Advisory Committee Recommends Tysabri Return