Dear Bloggers, we are away for all of this week, in Canada……back in October.

Serious HealthCare Issues – Part One

Former Cigna VP Speaks Out

Serious HealthCare Issues – Part Two

Former Cigna VP Speaks Out

Target Health Writeup in ClinPage

Target Health is pleased to announce that Mark Uehling, author of ClinPage, has written an article entitled On Target at Target Health in the September 25, 2009 edition of the website.  Here is part of the article 

Target Health’s president Jules Mitchel has been having a great year. His small, New York-based contract research organization has been posting some numbers that far larger contract research firms would be very happy with. “We have three approvals with EDC this year already,” Mitchel notes, referring to his customer’s progress in Europe and at the FDA. “We have three approvals with 42 employees. Last year, we had two approvals.” In his spare time, Mitchel has been a pioneer in developing software for electronic data capture and document management. “We give people what they need. Our system was developed by project managers and data managers, not technology people. We get repeat business all the time.” Of late, he’s been putting the finishing touches on a clinical trial management system (CTMS). The system doesn’t yet have a module to handle payments to sites. But it does the other work of a CTMS, helping to pick and manage sites. It handles drug supplies. Says Mitchel: “The documents and the CTMS should be controlled by the sponsors.” And on the topic of his CTMS, he is energized about the reports the system can produce, believing they are powerful enough to help projects run more smoothly. “This is across all studies,” he notes. “I can see all my deliverables.” Demonstrating the system for a reporter, he types in a name, and sees all of the work that that soul owes the trial. “We want to make everything transparent.” There are people in the industry who accommodate paper, indulge attachments, and generally don’t want to nudge the clinical trial fraternity toward an age of greater efficiency. For reasons we’ve never quite understood, Mitchel’s optimism extends toward pushing his own company and clients toward no paper. He doesn’t view this as a quixotic quest. He sees it as a matter of efficiency and getting therapies to market as rapidly as possible. “Our goal is to eliminate email and spreadsheets and all that stuff,” he says. Target Health is paperless, an achievement that is probably only possible at a small firm. Adds Mitchel: “We have no trial master file binders in the company. We sign everything electronically.” The company’s approach, he says, has now attracted a few other contract research organizations (CROs) that realize they need good tools, too. They’re using Target Health’s software. “Our business model is to partner,” he says. “We are partnering with several CROs. They may get projects they wouldn’t get without it.” In a separate initiative, Mitchel is exploring ways to connect clinical trials to electronic health records. He is not alone in this regard. But he believes the technical aspects of such linkages may be easier than much of the industry suspects. One of the most delicate issues is that the integrity of the clinical trial system has to be maintained, as the EHR industry remains unconcerned with the regulations around clinical trials. “The EHR companies claim they don’t want to be part 11 compliant,” he says. “So we are populating the EHR as opposed to having the EHR sending data to the EDC company.” 

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

NIH and Epigenomics

The NIH announced last week, that it will fund 22 grants on genome-wide studies of how epigenetic changes — chemical modifications to genes that result from diet, aging, stress, or environmental exposures — define and contribute to specific human diseases and biological processes. A 1) ___ is the complete set of DNA, in a cell. The epigenome consists of chemical compounds that modify, or mark, the genome in a way that tells it what to do, where to do it and when to do it. The marks, which are not part of the DNA itself, can be passed on from cell to cell as cells 2) ___, and from one generation to the next. The human body contains trillions of cells, all of which have essentially the same genome. Yet some cells are optimized for use in muscles, others for bones, the brain, the stomach and the rest of the body. Different sets of genes are turned on or off in various kinds of cells at different points in time. The epigenome influences which 3) ___ are active, and which proteins are produced in a particular cell. The epigenome signals, skin cells to behave like skin cells, same with heart cells, and all cells. The epigenome, marks the genome with its chemical tags. The epigenome also serves as the intersection between the genome and the 4) ___. The first type of mark, called DNA methylation, directly affects the DNA in a person’s genome. In this process, chemical tags called methyl groups attach to the backbone of the DNA 5) ___ in specific places. The methyl groups turn genes off or on by affecting interactions between DNA and the cell’s protein-making machinery. The second kind of mark, called histone modification, indirectly affects the DNA in the genome. Histones are spool-like 6) ___ that enable DNA’s very long molecules to be wound up neatly into chromosomes inside the cell nucleus. A variety of chemical tags can grab hold of the tails of histones, changing how tightly or loosely they package DNA. If the wrapping is tight, a gene may be hidden from the cell’s protein-making machinery, and consequently be switched off. In contrast, if the wrapping is loosened, a gene that was formerly hidden may be turned on. The chemical tags found on the DNA and histones of eggs and 7) ___ can be conveyed to the next generation. A genome contains two copies of every gene – one inherited from the mother and one from the father. For some genes, only the copy from the mother ever gets switched on, and for others, only the copy from the father. This pattern is called imprinting. The epigenome serves to distinguish between the two copies of an imprinted gene. For example, only the father’s copy of a gene called IGF2 is able to make its protein. That is because marks in the epigenome keep the mother’s IGF2 copy switched off in every cell of the body. Some diseases are caused by abnormal imprinting. Lifestyle and 8) ___ factors can expose a person to chemical tags that change the epigenome. The epigenome may change based on what a person eats and drinks, smokes, takes medicines, encounters pollutants, etc. There is also some evidence from animal and human studies that indicates that what a female eats and drinks during 9) ___ may change the epigenome of her offspring. Some epigenomic changes may trigger or increase the severity of disease. Researchers already have linked changes in the epigenome to various cancers, diabetes, autoimmune diseases and mental illnesses. A number of diseases and conditions to be studied under NIH grants will include tumor development, hardening of the arteries, autism, glaucoma, asthma, aging, and abnormal growth and development. These studies will help increase our understanding of how factors such as environmental exposures, alcohol, drug abuse and stress can modify the effect of epigenetics on diseases.

 

Answers: 1) genome; 2) divide; 3) genes; 4) environment; 5) molecules; 6) proteins; 7) sperm; 8) environmental; 9) pregnancy

Genes From 1630 and 2009

In the 1630s, the Fry family came to the New World with more than just dreams of prosperity and freedom. They also came with a genetic mutation that increased the likelihood of colon cancer in hundreds, if not thousands, of their descendants. The scientists who traced that gene back almost 370 years are now reporting that routine screening and education can prevent people with the mutated gene from developing cancer. Their new report on Mr. and Mrs. George Fry, who likely arrived in Massachusetts colony aboard the William & Mary, was presented in the Spring of 2009, at the 237th National Meeting of the American Chemical Society (ACS). Cancer records and a massive genealogic archive known as the Utah Population Database (UPDB) was used to trace the genetic condition to a Utah pioneer family and their 7,000 descendents. A New York family with the same genetic condition was also linked to the Utah group, which helped trace the two families back 16 generations to the Frys. The gene mutation causes a condition known as attenuated familial adenomatous polyposis (AFAP). AFAP causes the growth of colorectal polyps that have the potential to become cancerous. People with the AFAP mutation have about a two in three risk of getting colon cancer, compared to about one in 24 for the general population. Through molecular testing, Neklason was able to find 15 families with the identical genetic change who appeared to be related. The researchers studied approximately 200 of the Frys’ descendants with the genetic mutation from two different families in Utah and New York State, identifying genetic and lifestyle differences that increased the likelihood of polyps. The group identified a gene known as NAT1 that may influence polyp growth. Using an extensive diet questionnaire, they also found that a high fat diet and obesity lends itself to more polyps. On the other hand, fish fats, bananas, calcium, aspirin and caffeine demonstrated some protective effects.

HIV AIDS

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HIV Vaccine Regimen Demonstrates Modest Preventive Effect in Thailand Clinical Study

In an encouraging development, an investigational vaccine regimen has been shown to be well-tolerated and to have a modest effect in preventing HIV infection in a clinical trial involving more than 16,000 adult participants in Thailand. Following a final analysis of the trial data, the Surgeon General of the U.S. Army, the trial sponsor, announced today that the prime-boost investigational vaccine regimen was safe and 31% effective in preventing HIV infection. “These new findings represent an important step forward in HIV vaccine research,” says Anthony S. Fauci, M.D., director of the National Institute of Allergy and Infectious Diseases (NIAID), part of the NIH, which provided major funding and other support for the study. The Thai Phase III HIV vaccine study, also known as RV144, opened in October 2003. The placebo-controlled trial tested the safety and effectiveness of a prime-boost regimen of two vaccines: ALVAC-HIV vaccine (the primer dose), a modified canarypox vaccine developed by Sanofi Pasteur, based in Lyon, France, and AIDSVAX B/E vaccine (the booster dose), a glycoprotein 120 vaccine developed by Vaxgen Inc. The latter vaccine has been licensed to Global Solutions for Infectious Diseases (GSID), based in South San Francisco, CA. The vaccines are based on the subtype B and E HIV strains that commonly circulate in Thailand. The subtype B HIV strain is the one most commonly found in the United States. Led by principal investigator Supachai Rerks-Ngarm, M.D., of the Thai Ministry of Public Health’s Department of Disease Control, the study was sponsored by the U.S. Army in collaboration with NIAID, Sanofi Pasteur and GSID. The trial, conducted in the Rayong and Chon Buri provinces of Thailand, enrolled 16,402 men and women ages 18 to 30 years old at various levels of risk for HIV infection. Study participants received the ALVAC HIV vaccine or placebo at enrollment and again after 1 month, 3 months, and 6 months. The AIDSVAX B/E vaccine or placebo was given to participants at 3 and 6 months. Participants were tested for HIV infection every 6 months for 3 years. During each clinic visit, they were counseled on how to avoid becoming infected with HIV. In the final analysis, 74 of 8,198 placebo recipients became infected with HIV compared with 51 of 8,197 participants who received the vaccine regimen. This level of effectiveness in preventing HIV infection was found to be statistically significant. The vaccine regimen had no effect, however, on the amount of virus in the blood of volunteers who acquired HIV infection during the study. Individuals who acquired HIV infection while participating in the Thai trial have been provided access to HIV care and treatment, including highly active antiretroviral therapy based on the guidelines of the Thai Ministry of Public Health.

Electronic Nose Sniffs Out Toxins

Imagine a polka-dotted postage stamp-sized sensor that can sniff out some known poisonous gases and toxins and show the results simply by changing colors. Support for the development and application of this electronic nose comes from the National Institute of Environmental Health Sciences, part of the National Institutes of Health. The new technology is discussed in the September issue of Nature Chemistry and exemplifies the types of sensors that are being developed as part of the NIH Genes, Environment and Health Initiative (GEI) (http://www.gei.nih.gov/index.asp). Once fully developed, the sensor could be useful in detecting high exposures to toxic industrial chemicals that pose serious health risks in the workplace or through accidental exposure. While physicists have radiation badges to protect them in the workplace, chemists and workers who handle chemicals do not have equivalent devices to monitor their exposure to potentially toxic chemicals. The investigators have created what they refer to as an optoelectronic nose, an artificial nose for the detection of toxic industrial chemicals (TICs) that is simple, fast, inexpensive, and works by visualizing colors, and hope to be able to market the wearable sensor within a few years. The device has a disposable 36-dye sensor array that changes colors when exposed to different chemicals. The pattern of the color change is a unique molecular fingerprint for any toxic gas and also tells its concentration. By comparing that pattern to a library of color fingerprints, the device can identify and quantify the TICs in a matter of seconds. Older detection methods have relied on sensors whose response originates from weak and highly non-specific chemical interactions, whereas this new technology is more responsive to a diverse set of chemicals. The power of this sensor to identify so many volatile toxins stems from the increased range of interactions that are used to discriminate the response of the array. To test the application of their color sensor array, the study chose 19 representative examples of toxic industrial chemicals. Chemicals such as ammonia, chlorine, nitric acid and sulfur dioxide at concentrations known to be immediately dangerous to life or health were included. The arrays were exposed to the chemicals for two minutes. Most of the chemicals were identified from the array color change in a number of seconds and almost 90% of them were detected within two minutes. The laboratory studies used inexpensive flatbed scanners for imaging, but a fully functional prototype handheld device has been developed that uses inexpensive white LED illumination and an ordinary camera, which will make the whole process of scanning more sensitive, smaller, faster, and even less expensive. It will be similar to a card scanning device. One of the nice things about this technology is that it uses components that are readily available and relatively inexpensive. Given the broad range of chemicals that can be detected and the high sensitivity of the array to those compounds, it appears that this device will be particularly useful in occupational settings. Here is a link to photo of a postage stamp sized optical sensor array (small square silver colored device) for toxic gases and the sampled color changes associated with a few representative poison gases (chlorine, fluorine, hydrofluoric acid, hydrogen cyanide, B2H2, hydrazine, cobalt chloride, H2S, phosphine, ammonia, NO2, and sulphur dioxide).

Two Gene Variants Associated With Alzheimer’s Risk Identified

To date, only four genes have been definitively associated with Alzheimer’s disease (AD). Three mutated genes-amyloid precursor protein (APP) and the presenilins (PS1 and PS2)-have been shown to cause the rare, early-onset familial form of the disease, which mostly occurs in middle age. Only one gene variant, apolipoprotein e4 or APO-e4, has been confirmed as a significant risk factor gene for the common form of late-onset AD, which typically strikes after age 65. The goal of Genome-wide association (GWAS) studies is to look for genetic associations of diseases with the DNA of individuals within specific populations. To date, such studies have been done on relatively small numbers of samples and have not been able to identify genetic variations of smaller effect. In the largest GWAS reported to date involving AD (6 September 2009, online issue of Nature Genetics), two new possible genetic risk factors for late-onset AD, the most common form of the disease, have identified. Results showed that not only variations in the sequence of the CLU and PICALM genes were associated with increased risk, but that there were also 13 gene variants that merit further investigation. Involving more than 16,000 DNA samples, one feature of this research was its use of publicly shared DNA samples and databases, including several supported by the National Institute on Aging (NIA) and other components of the NIH. The study used brain and blood tissues made available and analyzed by dozens of laboratories in the United Kingdom, Ireland, Germany, Belgium, Greece and the US. The two-stage study first used samples from people with AD and a control group free of the disease to locate CLU on chromosome 8 and PICALM on chromosome 11, and then replicated the findings in a second stage of testing. CLU (ApoJ/clusterin located on chromosome 8) and PICALM (phosphatidylinositol-binding clathrin assembly protein located on chromosome 11) are both potentially involved in important pathways involved in AD. While more study is needed to determine the roles of the CLU and PICALM variants in AD pathology, the study noted that CLU levels are often elevated when brain tissue is injured or inflamed. Increased levels of CLU are found in the brains and cerebrospinal fluids of AD patients. Neurons have trouble functioning in neurodegenerative diseases because as the disease progresses, the connections between neurons, or synapses, often break down. Senile plaques and associated beta-amyloid are another hallmark of AD. It has been hypothesize that PICALM may play a role in synaptic health and that it may also affect the levels of beta-amyloid deposits in the brain.

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 New Drug to Treat Psoriasis

Plaque psoriasis is an immune system disorder that results in the rapid overproduction of skin cells. About 6 million people in the US have plaque psoriasis which is characterized by thickened patches of inflamed, red skin, often covered with silvery scales. The FDA has approved Stelara (ustekinumab), a biologic product for adults who have a moderate to severe form of psoriasis. Stelara is a monoclonal antibody, a laboratory-produced molecule that mimics the body’s own antibodies that are produced as part of the immune system. The biologic treats psoriasis by blocking the action of two proteins which contribute to the overproduction of skin cells and inflammation. Three studies of 2,266 patients evaluated the biologic’s safety and effectiveness. Since Stelara reduces the immune system’s ability to fight infections, the product poses a risk of infection. Serious infections have been reported in patients receiving the product and some of them have lead to hospitalization. These infections were caused by viruses, fungi, or bacteria that have spread throughout the body. There may also be an increased risk of developing cancer. The FDA is requiring a risk evaluation and mitigation strategy or REMS for Stelara that includes a communication plan targeted to healthcare providers and a medication guide for patients. Stelara is manufactured by Centocor Ortho Biotech Inc. of Horsham, Pa., a wholly-owned subsidiary of Johnson & Johnson of New Brunswick, N.J.

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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