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Contents
Sugar Pill Problem for Big Pharma Pharma and Biotech Industry Vertical Farming is the Solution Failures of Big Pharma FDA Approvals for August Ocimum Biosolutions Pain Medication for Dogs FDA 505(b)(2) Approval for Teva Alzheimer's Disease Research Sugar Pill Problem for Big Pharma Spoonful of sugar helps the medicine go down The medicine go down-wown The medicine go down Just a spoonful of sugar helps the medicine go down In a most delightful way! (Mary Poppins) The classic use of placebos in medicine—to boost the confidence of anxious patients—has been employed tacitly for ages. Nearly half of the doctors polled in a 2007 survey in Chicago admitted to prescribing medications they knew were ineffective for a patient's condition—or prescribing effective drugs in doses too low to produce actual benefit—in order to provoke a placebo response. The fact that taking a sugar pill can powerfully improve some people's health—the so-called placebo effect—has long been considered an embarrassment to the serious practice of pharmacology. Ironically, Big Pharma's attempt to dominate the central nervous system has ended up revealing how powerful the brain really is. The placebo response doesn't care if the catalyst for healing is a triumph of pharmacology, a compassionate therapist, or a syringe of salt water. All it requires is a reasonable expectation of getting better. That's potent medicine. The roots of the placebo response can be traced to a lie told by an Army nurse during World War II as Allied forces stormed the beaches of southern Italy. The nurse was assisting an anesthetist named Henry Beecher, who was tending to US troops under heavy German bombardment. When the morphine supply ran low, the nurse assured a wounded soldier that he was getting a shot of potent painkiller, though her syringe contained only salt water. Amazingly, the bogus injection relieved the soldier's agony and prevented the onset of shock. Returning to his post at Harvard after the war, Beecher became one of the nation's leading medical reformers. Inspired by the nurse's healing act of deception, he launched a crusade to promote a method of testing new medicines to find out whether they were truly effective. At the time, the process for vetting drugs was sloppy at best: Pharmaceutical companies would simply dose volunteers with an experimental agent until the side effects swamped the presumed benefits. Beecher proposed that if test subjects could be compared to a group that received a placebo, health officials would finally have an impartial way to determine whether a medicine was actually responsible for making a patient better. In a 1955 paper titled "The Powerful Placebo," published in The Journal of the American Medical Association, Beecher described how the placebo effect had undermined the results of more than a dozen trials by causing improvement that was mistakenly attributed to the drugs being tested. He demonstrated that trial volunteers who got real medication were also subject to placebo effects; the act of taking a pill was itself somehow therapeutic, boosting the curative power of the medicine. Only by subtracting the improvement in a placebo control group could the actual value of the drug be calculated. The article caused a sensation. By 1962, reeling from news of birth defects caused by a drug called thalidomide, Congress amended the Food, Drug, and Cosmetic Act, requiring trials to include enhanced safety testing and placebo control groups. Volunteers would be assigned randomly to receive either medicine or a sugar pill, and neither doctor nor patient would know the difference until the trial was over. Beecher's double-blind, placebo-controlled, randomized clinical trial—or RCT—was enshrined as the gold standard of the emerging pharmaceutical industry. Today, to win FDA approval, a new medication must beat placebo in at least two authenticated trials. Beecher's prescription helped cure the medical establishment of outright quackery. The triumph of Beecher's gold standard was a generation of safer medications that worked for nearly everyone. Anthracyclines don't require an oncologist with a genial bedside manner to slow the growth of tumors. What Beecher didn't foresee, however, was the explosive growth of the pharmaceutical industry. The blockbuster success of mood drugs in the '80s and '90s emboldened Big Pharma to promote remedies for a growing panoply of disorders that are intimately related to higher brain function. By attempting to dominate the central nervous system, Big Pharma gambled its future on treating ailments that have turned out to be particularly susceptible to the placebo effect. From 2001 to 2006, the percentage of new products cut from development after Phase II clinical trials, when drugs are first tested against placebo, rose by 20 percent. The failure rate in more extensive Phase III trials increased by 11 percent, mainly due to surprisingly poor showings against placebo. Despite historic levels of industry investment in R&D, the US Food and Drug Administration approved only 19 first-of-their-kind remedies in 2007—the fewest since 1983—and just 24 in 2008. Half of all drugs that fail in late-stage trials drop out of the pipeline due to their inability to beat sugar pills. Why are inert pills suddenly overwhelming promising new drugs and established medicines alike? The reasons are only just beginning to be understood. A network of independent researchers is doggedly uncovering the inner workings—and potential therapeutic applications—of the placebo effect. At the same time, drugmakers are realizing they need to fully understand the mechanisms behind it so they can design trials that differentiate more clearly between the beneficial effects of their products and the body's innate ability to heal itself. A special task force of the Foundation for the National Institutes of Health is seeking to stem the crisis by quietly undertaking one of the most ambitious data-sharing efforts in the history of the drug industry. After decades in the jungles of fringe science, the placebo effect has become the elephant in the boardroom. Part of the problem was that response to placebo was considered a psychological trait related to neurosis and gullibility rather than a physiological phenomenon that could be scrutinized in the lab and manipulated for therapeutic benefit. But then Benedetti came across a study, done years earlier, that suggested the placebo effect had a neurological foundation. US scientists had found that a drug called naloxone blocks the pain-relieving power of placebo treatments. The brain produces its own analgesic compounds called opioids, released under conditions of stress, and naloxone blocks the action of these natural painkillers and their synthetic analogs. The study gave Fabrizio Benedetti at the University of Turin the lead he needed to pursue his own research while running small clinical trials for drug companies. Now, after 15 years of experimentation, he has succeeded in mapping many of the biochemical reactions responsible for the placebo effect, uncovering a broad repertoire of self-healing responses. Placebo-activated opioids, for example, not only relieve pain; they also modulate heart rate and respiration. The neurotransmitter dopamine, when released by placebo treatment, helps improve motor function in Parkinson's patients. Mechanisms like these can elevate mood, sharpen cognitive ability, alleviate digestive disorders, relieve insomnia, and limit the secretion of stress-related hormones like insulin and cortisol. William Potter, working on new antidepressants and antianxiety meds, became one of the first researchers to glimpse the approaching storm. As a psychiatrist, Potter knew that some patients really do seem to get healthier for reasons that have more to do with a doctor's empathy than with the contents of a pill. But it baffled him that drugs he'd been prescribing for years seemed to be struggling to prove their effectiveness. Thinking that something crucial may have been overlooked, Potter tapped an IT geek named David DeBrota to help him comb through the Lilly database of published and unpublished trials—including those that the company had kept secret because of high placebo response. They aggregated the findings from decades of antidepressant trials, looking for patterns and trying to see what was changing over time. What they found challenged some of the industry's basic assumptions about its drug-vetting process. Assumption number one was that if a trial were managed correctly, a medication would perform as well or badly in a Phoenix hospital as in a Bangalore clinic. Potter discovered, however, that geographic location alone could determine whether a drug bested placebo or crossed the futility boundary. By the late '90s, for example, the classic antianxiety drug diazepam (also known as Valium) was still beating placebo in France and Belgium. But when the drug was tested in the US, it was likely to fail. Conversely, Prozac performed better in America than it did in western Europe and South Africa. It was an unsettling prospect: FDA approval could hinge on where the company chose to conduct a trial. Mistaken assumption number two was that the standard tests used to gauge volunteers' improvement in trials yielded consistent results. Potter and his colleagues discovered that ratings by trial observers varied significantly from one testing site to another. It was like finding out that the judges in a tight race each had a different idea about the placement of the finish line. The geographic variations in trial outcome that Potter uncovered begin to make sense in light of discoveries that the placebo response is highly sensitive to cultural differences. Anthropologist Daniel Moerman found that Germans are high placebo reactors in trials of ulcer drugs but low in trials of drugs for hypertension—an undertreated condition in Germany, where many people pop pills for herzinsuffizienz, or low blood pressure. Moreover, a pill's shape, size, branding, and price all influence its effects on the body. Soothing blue capsules make more effective tranquilizers than angry red ones, except among Italian men, for whom the color blue is associated with their national soccer team—Forza Azzurri! Potter and DeBrota's data-mining also revealed that even superbly managed trials were subject to runaway placebo effects. But exactly why any of this was happening remained elusive. Ten years and billions of R&D dollars after Potter first sounded the alarm about the placebo effect, his message has finally gotten through. In the spring, Potter, who is now a VP at Merck, helped rev up a massive data-gathering effort called the Placebo Response Drug Trials Survey. Under the auspices of the NIH, Potter and his colleagues are acquiring decades of trial data—including blood and DNA samples—to determine which variables are responsible for the apparent rise in the placebo effect. Merck, Lilly, Pfizer, AstraZeneca, GlaxoSmithKline, Sanofi-Aventis, Johnson & Johnson, and other major firms are funding the study. The pharma crisis has also finally brought together the two parallel streams of placebo research—academic and industrial. Pfizer has asked Fabrizio Benedetti to help the company figure out why two of its pain drugs keep failing. Ted Kaptchuk is developing ways to distinguish drug response more clearly from placebo response for another pharma house that he declines to name. Both are exploring innovative trial models that treat the placebo effect as more than just statistical noise competing with the active drug. http://www.wired.com/medtech/drugs/magazine/17-09/ff_placebo_effect/?currentPage=1 Pharma and Biotech Industry Since Q4 2007, research spending in the U.S. has dropped 4 percent--or $1.9 billion. But a report in BusinessWeek lists 25 major U.S. corporations that, despite the economic downturn, have boosted R&D spending significantly in 2009. Of those 25, 13 were biotech and pharmaceutical companies, with Merck taking the top spot for increased spending. By comparison, only eight tech companies made the list. The reasons for the spending come back to the much-talked-about patent cliff. Big Pharma is increasing R&D so its pipeline is sufficient to replace the billions of dollars in products that are going off-patent over the next few years. Some of that money is being used to mine the industry for licensing deals, while other companies are simply spending more on clinical trials as products in their pipeline advance to later stages. The industry's buyout spree has also contributed to an increased R&D budget. More R&D spending may not solve the industry's problems though. Critics note that pumping more money into research has not resulted in more sales, and the industry's new drug offerings have dropped. Merck (up $371 million from 2008), Biogen Idec ($185.4 million), Eli Lilly ($159.1 million), Bristol-Myers Squibb ($144 million), and Gilead ($98.6 million) were the top five companies to make the list. View this chart (http://www.businessweek.com/table/09/0827_biotech_research_spending.html) to see data on all 25 companies. http://www.businessweek.com/bwdaily/dnflash/content/aug2009/db20090827_362578.htm Vertical Farming is the Solution The floods and droughts that have come with climate change are wreaking havoc on traditional farmland. Three recent floods (in 1993, 2007 and 2008) cost the United States billions of dollars in lost crops, with even more devastating losses in topsoil. Changes in rain patterns and temperature could diminish India’s agricultural output by 30 percent by the end of the century. What’s more, population increases will soon cause our farmers to run out of land. The amount of arable land per person decreased from about an acre in 1970 to roughly half an acre in 2000 and is projected to decline to about a third of an acre by 2050, according to the United Nations. With billions more people on the way, before we know it the traditional soil-based farming model developed over the last 12,000 years will no longer be a sustainable option. Irrigation now claims some 70 percent of the fresh water that we use. After applying this water to crops, the excess agricultural runoff, contaminated with silt, pesticides, herbicides and fertilizers, is unfit for reuse. The developed world must find new agricultural approaches before the world’s hungriest come knocking on its door for a glass of clean water and a plate of disease-free rice and beans. Imagine a farm right in the middle of a major city. Food production would take advantage of hydroponic and aeroponic technologies. Both methods are soil-free. Hydroponics allows us to grow plants in a water-and-nutrient solution, while aeroponics grows them in a nutrient-laden mist. These methods use far less water than conventional cultivation techniques, in some cases as much as 90 percent less. Now apply the vertical farm concept to countries that are water-challenged — the Middle East readily comes to mind — and suddenly things look less hopeless. For this reason the world’s very first vertical farm may be established there, although the idea has garnered considerable interest from architects and governments all over the world. Vertical farms are now feasible, in large part because of a robust global greenhouse initiative that has enjoyed considerable commercial success over the last 10 years. (Disclosure: I’ve started a business to build vertical farms.) There is a rising consumer demand for locally grown vegetables and fruits, as well as intense urban-farming activity in cities throughout the United States. Vertical farms would not only revolutionize and improve urban life but also revitalize land that was damaged by traditional farming. For every indoor acre farmed, some 10 to 20 outdoor acres of farmland could be allowed to return to their original ecological state (mostly hardwood forest). Abandoned farms do this free of charge, with no human help required. A vertical farm would behave like a functional ecosystem, in which waste was recycled and the water used in hydroponics and aeroponics was recaptured by dehumidification and used over and over again. The technologies needed to create a vertical farm are currently being used in controlled-environment agriculture facilities but have not been integrated into a seamless source of food production in urban high-rise buildings. Such buildings, by the way, are not the only structures that could house vertical farms. Farms of various dimensions and crop yields could be built into a variety of urban settings — from schools, restaurants and hospitals to the upper floors of apartment complexes. By supplying a continuous quantity of fresh vegetables and fruits to city dwellers, these farms would help combat health problems, like Type II diabetes and obesity, that arise in part from the lack of quality produce in our diet. Read the article at: http://www.nytimes.com/2009/08/24/opinion/24Despommier.html?_r=1&scp=1&sq=A%20Farm%20on%20Every%20Floor&st=cse Failures of Big Pharma Faced with a disappointing set of late-stage data, Eli Lilly has stopped work on the osteoporosis drug arzoxifene--a program that had been counted as one of its top three near-term drug prospects. After a five-year study dubbed Generations, Lilly researchers concluded that the drug did not prevent a variety of secondary conditions, including nonspinal fractures. The therapy also raised the risk of blood clots and hot flashes. http://www.bloomberg.com/apps/news?pid=20601103&sid=a2EhgicDWDzA A first-of-its-kind osteoporosis drug lowers the risk of bone fractures as well as or better than current medicines, studies in older women and men with prostate cancer suggest. Wall Street sees Amgen Inc.'s genetically engineered denosumab as a potential blockbuster crucial to the company's future. But given the crowded market of treatments for the bone-thinning disease, doctors see its expected high cost as a big drawback. The effectiveness of denosumab and existing drugs appears to plateau after two or three years. Global sales of osteoporosis treatments, including hundreds of vitamin brands, exceeded $8.3 billion last year, according to data from IMS Health. About 10 million Americans have osteoporosis, and another 44 million are at increased risk because of low bone density. India's Glenmark Pharmaceuticals and its U.S. partner Forest Laboratories revealed that their experimental COPD drug failed a Phase IIb trial. While well tolerated at all dose levels, researchers said that oglemilast--Glenmark's lead development program--failed to post a statistically significant efficacy outcome. http://online.wsj.com/article/SB125065856551642397.html?mod=googlenews_wsj Italy's Gentium saw its shares sag on the news that its experimental therapy to treat the blockage of small veins in the liver failed the primary and secondary endpoints of a late-stage trial. The veno-occlusive disease treatment defibrotide demonstrated "strong trends" in its favor, but failed to deliver the necessary data for complete response following 100 days after a stem cell transplant compared to patients receiving a best-care drug as well as an improved survival rate after 100 days and six months following treatment. http://www.reuters.com/article/governmentFilingsNews/idUSBNG47362120090819 Johnson & Johnson's drug development unit has been slapped with a warning letter saying that it "did not adhere to the applicable statutory requirements and FDA regulations governing the conduct of clinical investigations." http://www.reuters.com/article/rbssHealthcareNews/idUSN1841534620090818 Johnson & Johnson is consolidating management, starting by eliminating the smallest of its four business groups, with more changes expected over the next several weeks. In a strike against GlaxoSmithKline's Avandia, a new study found that it carries more heart risks than rival Actos. http://lists.fiercemarkets.com/c.html?rtr=on&s=69l,18enm,8ku,gcuz,kc6c,jbrk,by1k In a landmark case that has sparked a heated debate about patent linkage in India, Delhi's high court threw out Bayer's petition to block Indian generics maker Cipla from gaining regulatory approval for its version. http://www.fiercepharma.com/story/indian-court-dismisses-bayers-nexavar-patent-claim/2009-08-18 The JAMA delivered a mixed blessing to Merck's Gardasil. In a headliner study published by the Journal of the American Medical Association, the side effects of the human papillomavirus shot were deemed reasonable. And another JAMA study dropped a bombshell: Merck gave money to three medical societies to fund their promotion of Gardasil. http://www.fiercepharma.com/story/jama-gardasil-safe-promos-questionable/2009-08-19 Sanofi-aventis said that it would close its Kansas City manufacturing facility. The operation employs about 370 workers, a company spokesman said. Boehringer Ingelheim will ax between 600 and 900 pharmaceutical sales reps as the company heads over a generic cliff in 2010, according to Pharmagossip and CafePharma. Pharmagossip reported that “600 or more” reps got the ax recently. The manufacturing debacle unfolding at Genzyme Corp is not just hurting its bottom line: it threatens to dent the company's reputation for years to come. Genzyme, which is one of the world's biggest and most respected biotech companies, halted production in June at its Allston Landing plant in Boston due to contamination caused by a virus. The shut-down led to shortages of two of its biggest drugs: Cerezyme for Gaucher disease and Fabrazyme for Fabry disease, two rare genetic disorders. The drugs generated $1.7 billion of sales in 2008. Valeant Pharmaceuticals International said preliminary results showed its experimental drug for the treatment of pain associated with shingles failed to meet the main goal of a mid-stage trial. Eli Lilly and Co said it has offered buyouts to 4,000 of its U.S. sales representatives, in hopes several hundred of them will accept the offers ahead of a planned company restructuring. Employees who accept the buyout will be offered the company's standard severance package plus additional four months pay. Lilly employees have been notified that the restructuring, to be announced in November and begin in January, will reduce the size of its sales territories. FDA Approvals for August http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Reports.MonthlyApprovalsAll Ocimum Biosolutions Ocimum Biosolutions is a global integrated genomics services company with over 250 employees in Gaithersburg, MD in the US; Hyderabad, India; and The Netherlands. Ocimum provides comprehensive genomic reference databases, life science lab information management solutions, GLP-compliant microarray services and essential research consumables. Ocimum's BioExpress® and ToxExpress® are genomic services. Ocimum has been consistently ranked as India’s fastest growing biotechnology company and one of the fastest growing technology companies in Asia over the last four years by Deloitte Touche Tohmatsu. Ocimum Biosolutions, a leading integrated life sciences solutions company, has been listed in the third annual Inc. 5000, an exclusive ranking of the America’s fastest-growing private companies. The list represents the most comprehensive look at the most important segment of the economy—America’s independent-minded entrepreneurs. Anu Acharya is the founder and CEO of Ocimum Biosolutions. The company was founded in the year 2000 and has completed 3 international acquisitions, Gene Logic Genomics from Maryland, USA in the year 2007, Isogen Life Sciences from the Netherlands in 2006 and the GD business of MWG Biotech of Germany in 2005. Pain Medication for Dogs Abbott has partnered with Velcera, Inc., a specialty pharmaceutical company focused on pet health, to market the first canine pain management product delivered in a transmucosal mist form. Currently in clinical trials, the product combines the proven pain medication meloxicam, a nonsteroidal anti-inflammatory drug (NSAID) with Velcera's patented Promist(TM) technology, and has been globally licensed for pain management in dogs. FDA 505(b)(2) Approval for Teva Teva Pharmaceutical Industries Ltd. announced U.S. Food and Drug Administration (FDA) approval and launch of Oxaliplatin Injection. Teva’s 505(b)(2) New Drug Application provides for the use of Oxaliplatin Injection, 50 mg/10 mL and 100 mg/20 mL for adjuvant treatment of stage III colon cancer in patients who have undergone complete resection of the primary tumor and treatment of advanced colorectal cancer. In June, the U.S. District Court for the District of New Jersey granted summary judgment in Teva's favor on the issue of non-infringement with regard to Debiopharm's U.S. Patent No. 5,338,874. The patent is listed in the Orange Book for Sanofi-Aventis' Eloxatin® (oxaliplatin injection) which had annual sales of approximately $1.3 billion in the United States for the twelve months that ended December 31, 2008, based on IMS sales data. Sanofi-Aventis and Debiopharm have appealed this decision. Sanofi-Aventis has also sued the FDA seeking to rescind all approvals granted to date for Oxaliplatin Injection pending resolution of the outstanding appeal. Alzheimer's Disease Research A new class of molecules capable of blocking the formation of specific protein clumps that are believed to contribute to the dementia of Alzheimer’s disease (AD) patients has been discovered by researchers at the University of Pennsylvania School of Medicine and the National Institutes of Health (NIH) Chemical Genomics Center (NCGC). By assaying close to 300,000 compounds, the team has identified drug-like inhibitors of AD tau protein clumping, as reported in the journal Biochemistry. The researchers found a total of 285 compounds that were of potential interest, and of these they focused on a specific chemical series called ATPZs that effectively block fibril formation. The ATPZs fit most of the criteria for potential drug candidacy such as proper size, desirable chemical properties, specificity for the tau protein, and a predicted likelihood of crossing the blood-brain barrier. Tau fibrils accumulate as insoluble deposits in brain nerve cells of patients with a host of debilitating neurodegenerative diseases, the most prevalent of which is AD. Since these tau aggregates are found in several neurodegenerative disorders and are thought to contribute to disease pathology, it is hoped that drugs that prevent these deposits might prove to be effective therapeutic agents for AD and related disorders. Source: The primary sources cited above, BBC News, New York Times (NYT), Washington Post (WP), Mercury News, Bayarea.com, Chicago Tribune, CNN, USA Today, Intellihealthnews, Deccan Chronicle (DC), the Hindu, Hindustan Times, Times of India, AP, Reuters, AFP, Biospace etc. Notice: The content of the articles is intended to provide general information. 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