Target Health and ON TARGET Are Going On Vacation

 

Happy Holidays to all. The office will be closed as we will be taking a much needed break between December 25 and January 3rd 2010. However, as always, if you need us, emails and cell phones will be operational.

 

Fortunately, and because of a lot of hard work, this was a good year for Target Health and our clients. We were directly responsible for 4 regulatory approvals, (2 in the US, 1 in Canada and 1 in Europe), 2 eCTD NDA submissions, completion of a 90 center study in ulcerative colitis, release of 2 new software products, multiple FDA meetings and a growth of 10% including hiring of six new staff. In addition to the above, a major highlight was the finalization of the development and marketing partnership between Pfizer and Protalix Ltd. for a drug for the treatment of Gaucher’s disease. For this program, we had a true partnership with Protalix from the pre-IND meeting in June 2004 to the NDA submission in December 2009 (NDA submitted, just three months after last patient last visit). Part of Pfizer’s due diligence was a review of the entire paperless Trial Master File in Target Document, as well as asking us to share candidly our experience for this drug development program. We now look forward to a new collaboration with Pfizer and Protalix in both the clinical and regulatory areas.

 

For more information about Target Health and our software tools for paperless clinical trials, please contact Dr. Jules T. Mitchel (212-681-2100 ext 0) or Ms. Joyce Hays. Target Health’s software tools are designed to partner with both CROs and Sponsors. Please visit the Target Health Website at: www.targethealth.com

Slowing Evolution to Stop Drug Resistance

 

Infectious organisms that become resistant to 1) ___ are a serious threat to human society. They are also a natural part of evolution. In a new project, researchers at the University of Gothenburg are attempting to find substances that can slow the pace of evolution, in order to ensure that the drugs of today remain effective into the future. The resistance of infectious 2) ___ to antibiotics is particularly serious in drugs against fungi. Fungal cells are similar to human cells,which means that it is difficult to develop effective drugs that can destroy them without also damaging human cells. We must, therefore, safeguard the effectiveness of the few antifungal drugs that are available today. Resistance would leave many diseases without effective treatment. However, drug resistance is a natural part of evolution. Evolution creates random variations in the characteristics of organisms, which results in some of them developing greater tolerance to drugs to which they are exposed. This leads eventually to completely resistant fungal strains, and the drug will become totally ineffective. The quicker these random 3) ___ appear, the greater the risk of resistance developing. One way of combating drug resistance is to slow down the pace of evolution. Researcher Jonas Warringer at the Department of Cell and Molecular Biology is using advanced 4) ___ experiments to try to find such “evolution-slowing” substances. In the first instance, this involves identifying the cell components that regulate the speed of evolution. Warringer is using ordinary brewer’s yeast as a model for their studies. A yeast has 6,000 genes, and destroying single genes in otherwise identical organisms enables the use of method of exclusion. “We stimulate the evolution of the yeast cell and observe it in real time. As our yeasts develop 5) ___ to a particular drug, we measure how the survivability of the different strains changes during the process. Evolution progresses more slowly in some strains when a specific component is destroyed. These strains are like gold dust to us, because they tell us that these particular components are critical to the speed of evolution,” says Warringer. “This is how we eventually found the genes that regulate evolution. If, in the next phase, we can find a substance that can attack one of these components, we will be able to delay the development of drug resistance and ensure that today’s drugs remain effective into the future.” Warringer hopes that 6) ___-slowing drugs will become available within the next 10 years.

 

ANSWERS: 1) antibiotics; 2) organisms; 3) variations; 4) genetic; 5) resistance; 6) evolution

Tuberculosis Part 2

 

The study of tuberculosis (TB), sometimes known as phthisiatry, dates back to The Canon of Medicine written by Ibn Sina (Avicenna) in the 1020s. He was the first physician to identify pulmonary TB as a contagious disease and the first to develop the method of quarantine in order to limit its spread. In ancient times, treatments focused on sufferers’ diets. Pliny the Elder described several methods in his Natural History: “wolf’s liver taken in thin wine, the lard of a sow that has been fed upon grass, or the flesh of a she-ass taken in broth”. Although it was established that the pulmonary form was associated with “tubercles” by Dr Richard Morton in 1689, due to the variety of its symptoms, TB was not identified as a single disease until the 1820s and was not named “tuberculosis” until 1839 by J. L. Sch?nlein. During the years 1838-1845, Dr. John Croghan, the owner of Mammoth Cave, brought a number of TB sufferers into the cave in the hope of curing them with the constant temperature and purity of the cave air; they died within a year. The first TB sanatorium opened in 1854 in G?rbersdorf, Germany (today Sokolowsko, Poland) by Hermann Brehmer. The bacillus causing TB, Mycobacterium tuberculosis, was identified and described on 24 March 1882 by Robert Koch. He received the Nobel Prize in physiology or medicine in 1905 for this discovery. Koch did not believe that bovine (cattle) and human TB were similar, which delayed the recognition of infected milk as a source of infection. Later, this source was eliminated by the pasteurization process. Koch announced a glycerine extract of the tubercle bacilli as a remedy for TB in 1890, calling it “tuberculin”. It was not effective, but was later adapted as a test for pre-symptomatic TB. The first genuine success in immunizing against TB was developed from attenuated bovine-strain TB by Albert Calmette and Camille Gu?rin in 1906. It was called “BCG” (Bacillus of Calmette and Gu?rin). The BCG vaccine was first used on humans in 1921 in France, but it was not until after World War II that BCG received widespread acceptance in the USA, Great Britain, and Germany. In 1815, one in four deaths in England was from consumption; by 1918 one in six deaths in France were still caused by TB. In the 20th century, TB killed an estimated 100 million people. After the establishment in the 1880s that the disease was contagious, TB was made a notifiable disease in Britain; there were campaigns to stop spitting in public places, and the infected poor were pressured to enter sanatoria. Whatever the purported benefits of the fresh air and labor in the sanatoria, even under the best conditions, 50% of those who entered were dead within five years (1916). The promotion of Christmas Seals began in Denmark during 1904 as a way to raise money for TB programs. It expanded to the United States and Canada in 1907-1908 to help the National Tuberculosis Association (later called the American Lung Association). In the US, concern about the spread of TB played a role in the movement to prohibit public spitting except into spittoons. In Europe, deaths from TB fell from 500 out of 100,000 in 1850 to 50 out of 100,000 by 1950. TB remained such a significant threat to public health, that when the Medical Research Council was formed in Britain in 1913, its initial focus was TB research. It was not until 1946 with the development of the antibiotic streptomycin that effective treatment and cure became possible. Prior to the introduction of this drug, the only treatment besides sanatoria were surgical interventions, including the pneumothorax or plombage technique – collapsing an infected lung to “rest” it and allow lesions to heal – a technique that was of little benefit and was mostly discontinued by the 1950s. Hopes that the disease could be completely eliminated have been dashed since the rise of drug-resistant strains in the 1980s. For example, TB cases in Britain, numbering around 117,000 in 1913, had fallen to around 5,000 in 1987, but cases rose again, reaching 6,300 in 2000 and 7,600 cases in 2005. Due to the elimination of public health facilities in New York and the emergence of HIV, there was a resurgence of TB in the late 1980s. New York had to cope with more than 20,000 TB patients with multidrug-resistant strains (resistant to, at least, both Rifampin and Isoniazid). The resurgence of TB resulted in the declaration of a global health emergency by the World Health Organization (WHO) in 1993. Every year, nearly half a million new cases of multidrug-resistant TB (MDR-TB) are estimated to occur worldwide. TB has co-evolved with humans for many thousands of years, and perhaps for several million years. The oldest known human remains showing signs of TB infection are 9,000 years old. During this evolution, M. tuberculosis has lost numerous coding and non-coding regions in its genome, losses that can be used to distinguish between strains of the bacteria. The implication is that M. tuberculosis strains differ geographically, so their genetic differences can be used to track the origins and movement of each strain.

Amyloid Deposits In Cognitively Normal People May Predict Risk For Alzheimer’s Disease

 

According to two articles published online in the Archives of Neurology (14 December 2009), abnormal deposits of a protein are associated with increased risk of developing the symptoms of Alzheimer’s disease in asymptomatic people free of dementia. The studies linked higher amounts of the protein deposits in dementia-free people with greater risk for developing the disease, and with loss of brain volume and subtle declines in cognitive abilities. For the study, brain scans and other tests were used to explore the relationship between levels of beta-amyloid, a sticky protein that forms the hallmark plaques of Alzheimer’s disease, and dementia risk in cognitively normal people. Previous studies of brain pathology, cognitive testing, and brain imaging have for some time suggested that Alzheimer’s pathology causes changes to the brain many years before memory loss, confusion, and other symptoms of the disease are apparent. But it has remained difficult to accurately predict whether a cognitively normal person will-or will not-develop the disease. The study used a variety of measures to look for changes in the brain in the two studies, including positron emission tomography (PET) imaging using a radioactive form of Pittsburgh Compound B (PiB), an agent specially developed to detect levels of beta-amyloid protein in the living brain; magnetic resonance imaging (MRI) to measure brain volume; and standardized clinical tests of memory and thinking abilities to determine cognitive health. Previously, the link between beta-amyloid load and Alzheimer’s disease could only be confirmed at autopsy. The studies indicated that beta-amyloid might be present in the brain even in symptom-free people. In study 1, between 2004 and 2008, researchers used PiB scans to track 159 volunteers ages 51 to 88, who started the study with no signs of cognitive impairment, to see if there was a correlation between beta-amyloid levels and cognitive health. Over time, 23 participants developed mild impairments, and nine were eventually diagnosed with clinical Alzheimer’s disease. Compared with participants who remained cognitively normal, the nine who were eventually diagnosed clinically with Alzheimer’s disease had high levels of PiB binding in the brain and experienced cognitive decline as well as volume loss in the parahippocampal gyrus, a part of the brain that controls memory. However, not every person who had beta-amyloid deposition in the brain developed cognitive impairment. It was therefore concluded that Beta-amyloid deposition may be a risk factor for developing Alzheimer’s disease but its presence does not constitute a diagnostic finding. In the second study, in 135 cognitively normal older adults aged 65 to 88, the level of beta-amyloid as measured by PiB binding correlated with atrophy, or shrinkage, in many parts of the brain and to declines on memory and thinking tests over many years. Clearly, more study is needed in larger groups for longer periods, but these studies confirm the value of detecting and measuring amyloid load in the brains of living people as soon as possible.

GENETICS

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Gene Linked to a Rare Form of Progressive Hearing Loss in Males

 

According to an article published in the December 17, 2009 online issue of the American Journal of Human Genetics, it was reported that a gene associated with a rare form of progressive deafness in males has been identified. The gene, PRPS1, appears to be crucial in inner ear development and maintenance and encodes the enzyme phosphoribosylpyrophosphate (PRPP) synthetase 1, which produces and regulates PRPP (phospho-ribosylpyrophosphate), and appears to play a key role in inner ear development and maintenance. The four mutations identified in the PRPS1 gene cause a decrease in the production of the PRPP synthetase 1 protein that results in defects in sensory cells (called hair cells) in the inner ear. The PRPS1gene is associated with DFN2, a progressive form of deafness that primarily affects males. Boys with DFN2 begin to lose their hearing in both ears roughly between the ages of 5 and 15, and over the course of several decades will experience hearing loss that can range from severe to profound. Their mothers, who carry the defective PRPS1 gene, may experience hearing loss as well, but much later in life and in a milder form. Families with DFN2 have been identified in the United States, Great Britain, and China. Other mutations in the PRPS1 gene have been linked to neurodegenerative disorders such as Arts syndrome and a form of Charcot-Marie Tooth disease, both of which feature deafness in the constellation of symptoms. Knowing that a reduction in the amount of PRPP synthetase 1 is what causes deafness in DFN2, the research team is now exploring potential enzyme replacement therapies to either restore hearing or prevent further hearing loss in boys with DFN2. Since the PRPS1 mutations can be used as a genetic marker for DFN2, in the future at-risk boys could be tested at birth and immediately put on enzyme replacement therapy to reduce or prevent the hearing loss that would ordinarily come later in life. In addition, the knowledge that is gained about the mechanisms of PRPS1 potentially could be used to develop treatments to combat acquired hearing loss, such as the hearing loss caused by drugs that are used in some chemotherapy regimens and treatments for HIV/AIDS. These are powerful and helpful medications, but they have the unfortunate side effect of damaging, even killing, hair cells in the inner ear. The results from this study open the possibility for improving these life-saving treatments by eliminating or reducing the disabling side effect of hearing loss.

Association Between Carrier Screening and Incidence of Cystic Fibrosis
 

In northeastern Italy, Cystic Fibrosis (CF) birth incidence is monitored by means of a long-standing neonatal screening program. In the same area, two sections using different carrier detection approaches were identified – the western region, in which CF carrier tests are offered only to relatives of patients or to couples planning in vitro fertilization; and the eastern region, in which carrier testing is offered to relatives and carrier screening to infertile couples and to couples of reproductive age. According to an article published in the Journal of the American Medical Association (2009;302:2573-2579) a study was performed to evaluate the association between carrier screening and (CF) birth incidence. For the study, total of 779,631 newborns underwent CF neonatal screening between January 1993 and December 2007, of whom 195 had CF detected. Results showed a time-related decrease in birth incidence, with a mean annual percentage decrease of 0.16 per 10,000 neonates (P < .001). In the western region, 2,559 carrier tests were performed, 314 carriers were identified, and 9 carrier couples were detected. In the eastern region, 87,025 carrier tests were performed, 3650 carriers were identified, and 82 carrier couples were detected. The birth rate decrease was greater in the eastern region (decrease rate, 0.24 than in the western region (decrease rate, 0.04 P = .01). The increase in the number of screened carriers over time was significantly correlated with the decrease in CF birth incidence (correlation coefficient = -0.53; P = .003). According to the authors, in northeastern Italy, carrier screening was associated with a decrease in the incidence of CF.

TARGET HEALTH excels in Regulatory Affairs and works closely with many of its clients performing all FDA submissions. TARGET HEALTH receives daily updates of new developments at FDA. Each week, highlights of what is going on at FDA are shared to assure that new information is expeditiously made available.

 

FDA Approves Generic Aricept to Treat Alzheimer’s Disease – Time to Revisit the Generic Drug Approval Process

 

Alzheimer’s disease is an irreversible, progressive brain disease that slowly destroys memory and thinking skills and, eventually, the ability to carry out the simplest tasks of daily living. In most people with Alzheimer’s disease, symptoms first appear after age 60. Alzheimer’s disease is the most common cause of dementia among older people, but it is not a normal part of aging. Dementia refers to a decline in cognitive function that interferes with daily life and activities. Alzheimer’s disease starts in a region of the brain that affects recent memory, then gradually spreads to other parts of the brain. The FDA has approved the first generic versions of Aricept (donepezil hydrochloride) orally disintegrating tablets for the treatment of dementia related to Alzheimer’s disease. Orally disintegrating tablets dissolve on the tongue, without having to be swallowed whole. This may make it easier to take the medication for older or disabled patients who have difficulty swallowing. The generic donepezil hydrochloride orally disintegrating tablets, manufactured by Mutual Pharmaceutical of Philadelphia, have been approved in 5 milligram and 10 mg strengths.

 

Interestingly, all major pharmaceutical companies are now selling their drugs, whose patents have expired, under their own brands, and are no longer lying down and giving gifts to the generic industry. If priced properly, this would be a small price to pay to get the “real thing” for the consumer and insurance companies. In the opinion of Target Health, and with respect to FDA’s position on generic drugs, a bioequivalence study in normal volunteers does not provide enough science to justify efficacy and safety of a generic drug used to treat complex diseases. As a result, all generic drug companies should also be required to do a non-inferiority clinical trial for efficacy against the innovator as well as have a REMS (Risk Evaluation and Mitigation Strategy as required for the innovator (see the New York Times 19 December 2009 – Personal Business – “A New Disquiet About Generic Drugs,” by Leslie Alderman).

 

For more information about our expertise in Regulatory Affairs, please contact Dr. Jules T. Mitchel or Dr. Glen Park.

Target Health (www.targethealth.com) is a full service eCRO with full-time staff dedicated to all aspects of drug and device development. Areas of expertise include Regulatory Affairs, comprising, but not limited to, IND (eCTD), IDE, NDA (eCTD), BLA (eCTD), PMA (eCopy) and 510(k) submissions, Management of Clinical Trials, Biostatistics, Data Management, EDC utilizing Target e*CRF®, Project Management, and Medical Writing. Target Health has developed a full suite of eClinical Trial software including 1) Target e*CRF® (EDC plus randomization and batch edit checks), 2) Target e*CTMSTM, 3) Target Document®, 4) Target Encoder®, 5) Target Newsletter®, 6) Target e*CTRTM (electronic medical record for clinical trials). Target Health ‘s Pharmaceutical Advisory Dream Team assists companies in strategic planning from Discovery to Market Launch. Let us help you on your next project. 

 

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