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Chemotalk NewsletterChemotalk Newsletter, Vol. 71: March 1, 2014 March news, starting with yet another validation of a scary trend: DRUG SHORTAGES CONTINUE TO VEX DOCTORS Despite efforts by the Obama Administration to east shortages of critical drugs, shortfalls have persisted, forcing doctors to resort to rationing in some cases or to scramble for alternatives, a government watchdog agency said. The number of annual drug shortages -- both new and continuing ones -- nearly tripled from 2007 to 2012. In recent years, drug shortages have become an all but permanent part of the American medical landscape. He most common ones are for generic versions of sterile injectable drugs, partly because factories that make them are aging and prone to quality problems, causing temporary closings of production lines or even entire factories. The analysis of the United States Government Accountability Office, released Monday, was required by 2012 law that gave the Food and Drug Administration more power to manage shortages. The watchdog agency was designated to evaluate whether the F.D.A. had improved its response to the problem, among other things. The accountability office concluded that the F.D.A. was preventing may more shortages now than in the past -- 154 potential shortages in 2012 compared with just 35 in 2010 -- but that the total number of shortages has continued to grow, In 2012, the number of drugs in short supply, both new and long-term, was 456, the report said, up from 154 in 2007. Such drugs now include the heart medicine nitroglycerin, and cisatracurium, which is used to paralyze muscles during surgery and for patients on ventilators. "We are at a pubic health crisis when we don't have the medicines to treat acutely ill patients and we don't have the basics like intravenous fluids," said Erin Fox, a drug expert at the University of Utah whose data was used in the analysis. The most acute shortages now is that of basic IV fluids, she said. Dr. Douglas C. Throckmorton, a senor F.D.A. official who deals with shortages, pointed out in testimony at a Congressional hearing on the matter that the number of new shortages declines in 2012 for the first time in a number of years, and that 2013 data indicated a similar downward trend.* He said the agency, endowed with new powers under the 2012 law, has been able to manage shortages more aggressively. Manufacturers are now required to alert the agency of potential shortages before they happen. And agency officials have been careful when using their regulatory muscle. For example, in some cases where particles were found to be contaminated a drug that was in short supply, the agency allowed the company to filter the drug to avoid disrupting supplies instead of shutting down the production line altogether. What drives shortages is often a mystery. The drug industry rarely spells out the precise reason for a shortage citing its need to protect competitive trade information. The 2012 law required that companies provide the F.D.A. with a general reason, but Ms. Fox said it was often jot specific enough to understand the particular causes of a shortage. Dr. Throckmorton said that two-thirds of the production disruptions that led to shortages were caused by quality problems and efforts to fix them. Economic factors are also a contributing factor. Narrow profit margins are making some drug companies reluctant to invest in fixing old production facilities. Changes in Medicare reimbursement and the role of group purchasing organizations, which buy drugs on behalf of hospitals, could also be contributing, by further reducing prices that producers get for the drugs. And in a peculiarity of the generic drug industry, a drug is often made by only a few producers, making it difficult to mitigate the effects of a shortage when it happens. The accountability agency's report cited a study that found just three manufacturers produce 71% of the country's sterile injectable CANCER drugs in 2008. What is more, generic drug producers have significantly ramped up the number of drugs they are producing, pumping out many different drugs on a single production line, which stretches already limited factory capacity and creates a situation ripe for quality problems, the report said. One study it cited found that production in the sterile injectable market had increased by half between 2006 and 2012, without a similar rise in manufacturing capability. Manufacturers, motivated by profit, will often choose to increase production of higher profit drugs on their busy factory floors, even if that means risking a shortage of less profitable drugs. The accountability office praised by the F.D.A. for increased nimbleness, and acknowledged that it could not ultimately force drug companies to produce. But it said the agency needs to use its drug databases, not just to track which drugs are running low, but also to identify patterns that can help prevent shortages. * Really? It's getting better? Because this month is the second time in 6 months that my pharmacy had to scramble to find a month's supply of tamoxifen. * * * Just wondering, if Medicare is designed to take care of people over 65, why are its members constantly subjected to "surcharges" and other limits to treatment options? PLAN TO LIMIT SOME DRUGS IN MEDICARE IS CRITICIZED By Katie Thomas and Robert Pear An alliance of drug companies and patient advocates, joined by Democrats and Republicans in Congress, is fiercely opposing an Obama administration proposal that would allow insurers to limit Medicare coverage for certain classes of drugs, including those used to treat depression and schizophrenia. Opponents warn that the proposal, if enacted, could harm patients. Federal officials say it would lower costs and reduce overuse of the drugs. The proposed rule, which would lift a requirement that insurers cover "all or substantially all" drugs in certain treatment areas, is just one of a series of changes to the drug program that are being opposed by the unlikely alliance. Even insurers and drug benefit managers, who have previously supported added limits on drug coverage, oppose the rule. They object to provisions including changes to so-called preferred pharmacy networks, where consumers are steered toward a limited network of pharmacies, and to reducing the number of plans that insurers ca offer in anyone region. A House subcommittee plans to hold a hearing on the proposal and the rule is open for public comment until March 7. "We've been scratching our heads over this," said John J. Castellani, the chief executive of the Pharmaceutical Research and Manufacturers of America, the drug-industry trade group. Medicare Part D, he noted, is the rare government program that not only gets high marks from consumers but also has cost taxpayers millions of dollars less than originally expected. "Why is the administration trying to make such extensive changes to a program that isn't broken?" Mr., Castellani's organization was one of more than 2-- groups that signed a letter this week asking that the rule be withdrawn. Earlier this month, Republican and Democratic members of the Senate Finance Committee warned that the proposal could diminish access to needed medication" without saving much money. The administration's proposal would remove the protected status from three classes of drugs that has been in place since the program's inception in 2--6: immunosuppressant drugs used in TRANSPLANT patients, antidepressants and antipsychotic medicines. They include many well-known drugs, such as Wellbutrin, Paxil and Prozac to treat depression, and Abilify and Seroquel to treat schizophrenia. Three other categories -- cancer, H.I.V. and anti-seizure drugs -- would retain their status as protected classes and insurance companies would be required to continue covering nearly all drugs in those treatment areas. Medicare has traditionally required the broad coverage because patients with these conditions must often try several drugs before finding one that works. In proposing the change last month, the administration said that the policy was envisioned as a temporary measure to help east patients' transition to the new Medicare drug program, and that since then insurers had lost their leverage in negotiating with drug companies because the drug companies knew the insurers were required to cover their drug costs and were therefore less willing to offer lower prices. In its proposal, the Obama administration cited a 2008 study by the actuarial and consulting firm Milliman that showed that the six protected classes accounted for anywhere from 17% to 33% of total outpatient drug spending under Part D of Medicare. In addition, it said that the costs of those drugs were on average 10% higher than they would be without the requirement to cover substantially all drugs in these classes. The administration predicted savings for both beneficiaries and the Medicare program if prescription drug plans could remove some currently covered drug from their formularies. It could also give insurers additional tools to limit overuse of certain drugs, such as the prescribing of antipsychotic drugs to nursing-home patients with dementia, a common practice that is widely viewed as inappropriate. "We believe the Part D program has been a phenomenal success," said Jonathan Blum, principal deputy administrator of the Center for Medicare and Medicaid Services, which oversees the Part D program. But, he added, "We also see vulnerabilities in the program, and we have proposed for public input into ways to improve it." Leaders of numerous patient advocacy groups, many of whom met last week with White House officials to express concern about the proposed rule, said they were worried that patients could be harmed if the policy changed. "The proposal undermines a key protection for some of the sickest, most vulnerable Medicare beneficiaries," said Andrew Sperling, a lobbyist at the National Alliance on Mental Illness. Under the proposal, Mr. Sperling said, a Medicare drug plan could have a list of preferred drugs with just two medications to treat schizophrenia. That is inadequate, he said, because anti-psychotic drugs work in different side effects. "You get much better outcomes when a doctor can work with patients to figure out which medications will work best for them." In a letter written by members of the Senate Finance Committee, the senators suggested that the change could raise costs in other areas. "If beneficiaries do not have access to needed medication," the letter said, "costs will be incurred as a result of unnecessary and avoidable hospitalizations, physician visits and other medical interventions." The new federal health care law requires that Medicare drug plans include all drugs in certain categories and classes "of clinical concern," and it authorized the secretary of health and human services to identify those categories. Mr. Sperling said lawmakers had assumed that Medicare officials would keep the original six protected classes and add to them, not cut them. The administration proposal sets a high standard for designating protected classes, saying the drugs must be needed to prevent "hospitalization, persistent or significant disability or incapacity, or death" that would otherwise occur within a week. Emily Shetty, a lobbyist for the Leukemia and Lymphoma Society, said Medicare beneficiaries, who include older and disabled Americans, should be treated with special care. "They are a more vulnerable patient population as a whole, and having access to a full range of therapies is crucial to ensure that they are able to get the care that they need," she said. The Medicare Part D program is unusual in that it requires broad coverage of drugs in these categories. Commercial insurance plans, including those in the new marketplaces operating under the federal health care law, have more flexibility. Some drugs are simply not covered, and some plans require that patients and doctors go through additional steps -- such as trying other drugs first, or getting approval from the insurer -- before a drug will be paid for. Insurers and the companies that manage their rug benefits argue that this arrangement has worked well for consumers, ensuring that drugs are being used properly and helping to keep prices low. But others have identified what they describe as a worrying trend toward more limited drug coverage, and higher out-of-pocket costs for the most expensive drugs. The rule has some supporters, and many groups back some aspects of the proposal while opposing others. "Just because a program is popular doesn't mean that it's being run the most efficiently, and at the best value for taxpayers and patients," said B. Douglas Hoey, chief executive of the National Community Pharmacists Association, which supports many aspects of the rule. * * * EXPOSURE TO ACID TURNS ADULT CELLS INTO STEM CELLS An international team of scientists has found a new way to create stem cells without the use of an embryo or outside DNA--an advance in stem cell technology that doesn't carry the ethical concerns of embryonic stem cells or the safety issues of induced pluripotent stem cells. Stem cells have been alluring to both scientists and the general public ever since their discovery opened up the possibility of treating countless diseases and other medical conditions. But despite huge advances in stem cell research in recent years, obstacles remain. "Our research findings demonstrate that creation of an autologous pluripotent stem cell--a stem cell from an individual that has the potential to be used for a therapeutic purpose--without an embryo is possible. The fate of adult cells can be drastically converted by exposing mature cells to an external stress or injury," said senior author Dr. Charles Vacanti, director of the Laboratory for Tissue Engineering and Regenerative Medicine at Brigham and Women's Hospital in Boston, in a press release. Researchers at Brigham and Women's Hospital, Japan's Riken Center for Developmental Biology and Harvard University detailed their findings in the journal Nature. * * * And more about stem cells: STEM CELL SIGNALING PROTEIN SPURS CANCER SPREAD By Emily Mullin In a discovery that could have implications for LEUKEMIA treatment, investigators at the University of California, San Diego School of Medicine have linked a protein associated with a vital stem cell signal to CANCER growth. The protein, called Lis1, is essential to hematopoietic stem cell (HSC) function and blood formation. HSCs are stem cells in the blood that differentiate into all other blood cells. In a study published in Nature Genetics, researchers explain that Lis1 regulates the process of asymmetric division of HSCs, making sure that these stem cells turn into more specialized cells to provide the right balance of new blood cells. In asymmetric division, stem cells split into two cells with different characteristics--one becomes a permanently specialized cell type while the other remains undifferentiated and open for further divisions. When researchers deleted the Lis1 protein from mouse HSCs, differentiation of stem cells sped up, creating too many specialized cells and not enough undifferentiated stem cells, which eventually resulted in a bloodless mouse. Then, when the scientists tried blocking the Lis1 signaling pathway, they found that cancer stem cells were no longer able to renew themselves and spread. "In this sense, the effect Lis1 has on leukemic self-renewal parallels its role in normal stem cell self-renewal," said principal investigator Tannishtha Reya, a professor in the department of pharmacology, in a statement. "Our work shows that elimination of Lis1 potently inhibits cancer growth, and identifies Lis1 and other regulators of protein inheritance as a new class of molecules that could be targeted in cancer therapy." Reya said more research is needed to determine whether inhibiting Lis1 in cancer cells would produce negative side effects in normal cells as well. She said it's possible that drugs targeting Lis1 could be more specific and less toxic than some current hemotherapy agents that target the mechanism that controls cell division. Harvesting embryonic stem cells, which are able to differentiate into any type of human cells and are thus highly useful, can cause the destruction of the embryo. Controversy surrounding producing embryonic stem cells has led to a greater research focus on induced pluripotent stem cells, first engineered by Shinya Yamanaka at Kyoto University in Japan in 2006. The original reprogramming method uses viruses to introduce the new DNA information into adult cells. Though iPS cells don't raise the same ethical concerns linked to the use of human embryonic stem cells, they pose their own set of problems. The viruses that enter the adult cells have the potential to introduce foreign DNA and spur the growth of tumors instead of helping to grow healthy tissue. To create their new stem cells, researchers first tested mature adult cells in the lab, letting them multiply and stressing the cells close to death by exposing them to things like trauma, low oxygen levels and an acidic environment. Within a few days, the researchers discovered that the cells survived and recovered from the stressful stimulus by naturally reverting into a state that is equivalent to an embryonic stem cell. These embryonic-like cells were then able to redifferentiate and mature into any type of cell and grow into any type of tissue, depending on the environment into which they were placed. Next, investigators tested their theory in mice that had been genetically altered with a specific mutation to light up green under a specific wavelength of light. Using an acid shock treatment, they stressed the green fluorescent protein (GFP+) cells in the blood. Days after exposure to the acidic environment, the blood cells reverted back to an embryonic stem cell-like state. These stem cells then began growing in spherical clusters. Scientists took these cell clusters and implanted them into normal mouse embryos that had not been genetically engineered or given the acid bath to create a mixture of cells. The implanted clusters spawned GFP+ tissues in all organs tested, confirming that the cells were pluripotent. While there are still no FDA-approved therapies that use stem cells, the new research may give scientists a new way to engineer stem cell treatments for a variety of diseases and conditions using patients' own cells without the need for genetic manipulation. * * * Think Spring! * * * And if you have any thoughts of how this newsletter could be improved, please email me directly, at Elaine@elainejesmer.com. Elaine Jesmer
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