Dr. Jules T. Mitchel, President of Target Health Inc., has been asked to present an evocative talk on “The Paperless Clinical Trial – Clinical, Data Management and Regulatory Perspectives,“ at the Disruptive Innovations in Clinical Trials meeting on September 15 – 16, 2011, at the Loews Philadelphia Hotel, Philadelphia, PA.



This conference is a must for those of us who want to be on the cutting edge of clinical research.


Other topics include:


1. Challenges and Opportunities in Clinical Development

2. Innovations in Science Applied to Clinical Development

3. Innovations in Technology Applied to Clinical Development

4. New Business Models for Clinical Development


The conference is being led by our colleagues:


1. Puneet Sapra, Director, World Wide Business Development & Innovation, Pfizer, Inc.

2. John Orloff, MD, Senior VP, Global Development & Chief Medical Officer, Novartis Pharma AG

3. Craig H. Lipset, Head of Clinical Innovation, Development Operations, Pfizer, Inc.


To register, visit www.theconferenceforum.org or call 646-350-2580. If needed, we can get you a 25% discount.


For more information about Target Health contact Warren Pearlson (212-681-2100 ext. 104). For additional information about software tools for paperless clinical trials, please also feel free to contact Dr. Jules T. Mitchel or Ms. Joyce Hays. The Target Health software tools are designed to partner with both CROs and Sponsors. Please visit the Target Health Website, www.targethealth.com

Drilling Down on LDL





High cholesterol can cause damage by building up plaque inside the arteries, narrowing the space available for blood flow. As this condition worsens it can trigger heart disease. Because LDL particles appear harmless until they are within the blood vessel walls and oxidized by free radicals, it is postulated that ingesting antioxidants and minimizing free radical exposure may reduce LDL’s contribution to atherosclerosis


LDL particles vary in size and density, and studies have shown that a pattern that has more small dense LDL particles, called Pattern B, equates to a higher risk factor for CHD 1) ___ ___ ___ than does a pattern with more of the larger and less dense LDL particles (Pattern A). This is because the smaller particles are more easily able to penetrate the endothelium. Pattern I, for intermediate, indicates that most LDL particles are very close in size to the normal gaps in the 2) ___ (26 nm).According to one study, sizes 19.0 to 20.5 nm were designated as pattern B and LDL sizes 20.6-22 nm were designated as pattern A.


Some in the medical community have suggested the correspondence between Pattern B and CHD is stronger than the correspondence between the LDL number measured in the standard lipid profile test. Tests to measure these LDL subtype patterns have been more expensive and not widely available, so the common 3) ___ profile test is used more commonly. There has also been noted a correspondence between higher triglyceride levels and higher levels of smaller, denser LDL particles and alternately lower 4) ___ levels and higher levels of the larger, less dense LDL.


With continued research, decreasing cost, greater availability and wider acceptance of other lipoprotein subclass analysis assay methods, including NMR 5) ___ research studies have continued to show a stronger correlation between human clinically obvious cardiovascular event and quantitatively-measured particle concentrations. Because LDL particles can also transport cholesterol into the artery wall, retained there by arterial proteoglycans and attract macrophages that engulf the LDL particles and start the formation of 6) ___, increased levels are associated with atherosclerosis. Over time vulnerable plaques rupture, activate blood clotting and produce arterial stenosis, which if severe enough results in heart attack, stroke, and peripheral vascular disease symptoms and major debilitating events.


Increasing evidence has revealed that the concentration and size of the LDL particles more powerfully relates to the degree of atherosclerosis progression than the concentration of cholesterol contained within all the LDL particles.The healthiest pattern A, though relatively rare, is to have small numbers of large LDL 7) ___ and no small particles. Having small LDL particles, though common, is an unhealthy pattern B; high concentrations of small LDL particles (even though potentially carrying the same total cholesterol content as a low concentration of large particles) correlates with much faster growth of atheroma, progression of atherosclerosis and earlier and more severe cardiovascular disease events and death.


LDL particles pose a risk for cardiovascular disease when they invade the endothelium and become oxidized, since the oxidized forms are more easily retained by the proteoglycans. A complex set of biochemical reactions regulates the 8) ___ of LDL particles, chiefly stimulated by presence of necrotic cell debris and free radicals in the endothelium. Statins reduce high levels of LDL particles by inhibiting the enzyme HMG-CoA reductase in cells, the rate-limiting step of cholesterol synthesis. To compensate for the decreased cholesterol availability, synthesis of hepatic LDL receptors is increased, resulting in an increased clearance of LDL particles from the 9) ___.


ANSWERS: 1) coronary heart disease; 2) endothelium; 3) lipid; 4) triglyceride; 5) spectroscopy; 6) plaques; 7) particles; 8) oxidation; 9) blood

Hunting for a Mass Killer in Medieval Graveyards





Beneath the Royal Mint Court, diagonally across the street from the Tower of London, lie 1,800 mute witnesses to the foresight of the city fathers in the year 1348. Recognizing that the Black Death then scourging Europe would inevitably reach London, the authorities prepared a special cemetery in East Smithfield, outside the city walls, to receive the bodies of the stricken. By autumn, the plague arrived. Within two years, a third or so of London’s citizens had died, a proportion similar to that elsewhere in Europe. The East Smithfield cemetery held 2,400 of the victims, whose bodies were stacked five deep. The agent of the Black Death is assumed to be Yersinia pestis, the microbe that causes bubonic plague today. But the epidemiology was strikingly different from that of modern outbreaks. Modern plague is carried by fleas and spreads no faster than the rats that carry them can travel. The Black Death seems to have spread directly from one person to another.


Victims sometimes emitted a deathly stench, which is not true of plague victims today. And the Black Death felled at least 30% of those it inflicted, whereas a modern plague in India that struck Bombay in 1904, before the advent of antibiotics, killed only 3% of its victims. These differences, as well as the fear that the Black Death might re-emerge, have prompted several attempts to retrieve DNA from Black Death cemeteries. The latest of these attempts is reported last week in of The Proceedings of the National Academy of Sciences by a research team led by Hendrik N. Poinar of McMaster University in Ontario and Johannes Krause of the University of Tubingen in Germany.


This research team looked for surviving fragments of DNA in bones and teeth that archaeologists had excavated from the East Smithfield site in the 1980s. The DNA matched that of the modern-day microbe, confirming, as have several other studies, that Yersinia pestis was indeed the agent of the Black Death. Sharon DeWitte, a member of Dr. Poinar’s team, was one of several skeptics who had doubted the microbe’s role. “I’m very happy to find out I was wrong,” said Dr. DeWitte, a paleodemographer at the University of South Carolina. “In science, if you’re open to alternative possibilities, you can change your mind.” Dr. Poinar’s team also looked for the microbe’s DNA in another medieval London cemetery, that of St. Nicholas Shambles, which was closed before the Black Death struck. They found no sign of it there, indicating that Yersinia pestis was not already present in the English population before the Black Death, so it must have arrived from elsewhere.


If Yersinia pestis was indeed the cause of the Black Death, why were the microbe’s effects so different in medieval times? Its DNA sequence may hold the answer. Dr. Poinar’s team has managed to reconstruct a part of the microbe’s genetic endowment. Yersinia pestis has a single chromosome, containing the bulk of its genes, and three small circles of DNA known as plasmids. The team has determined the full DNA sequence of the plasmid known as pPCP1 from the East Smithfield cemetery. But, disappointingly, it turns out to be identical to the modern-day plasmid, so it explains none of the differences in the microbe’s effects.


Mark Achtman, an expert on plague who works at University College Cork in Ireland, said that the new study was “technologically interesting” but that a great deal more of the microbe’s DNA needed to be sequenced to obtain scientifically important results. The challenge in reconstructing the microbe’s DNA from the East Smithfield cemetery is that it is highly fragmented. The Yersinia pestis chromosome is 4,653,728 units of DNA in length, but the bits of DNA from the cemetery are no more than 50 to 60 units long. Determining the order of the chemical units in such fragments has become possible only in the last few years with the development of new DNA sequencing machines that work with short fragments.


Another technical challenge is to separate the plague DNA from that of the human and other microbial DNA in the ancient bones. One technique that Dr. Poinar’s team has used is to tether plasmid DNA from the modern plague microbe to plastic beads. DNA is quick to bind to strands of DNA of the complementary sequence, as in the DNA double helix. So the beads act as fishing rods to pull out the DNA of interest. Published: The New York Times, August/September 2011 By Nicholas Wade


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Genetic Link to Mesothelioma




Mesothelioma tumors are typically associated with asbestos and erionite exposure. Erionite, a naturally occurring mineral fiber similar to asbestos, is found in rock formations and volcanic ash. Deposits have been located in at least 12 states. Only a small fraction of individuals exposed to erionite or asbestos actually develop mesothelioma, one of the deadliest forms of cancer that kills about 3,000 people each year in the US, with half of those diagnosed dying within one year. Additionally, rates of new cases of mesothelioma in parts of the world, including Europe and China, have risen steadily over the past decade.


According to a study, published online in Nature Genetics (28 August 2011;DOI: 10.1038/ng.912), it was found that individuals who carry a mutation in a gene called BAP1 are susceptible to developing two forms of cancer – mesothelioma, and melanoma of the eye. Additionally, when these individuals are exposed to asbestos or similar mineral fibers, their risk of developing mesothelioma, an aggressive cancer of the lining of the chest and abdomen, may be markedly increased. The study describes two US families with a high incidence of mesothelioma, as well as other cancers, associated with mutations of the BAP1 gene.


The study found evidence that some people with BAP1 gene mutations also developed breast, ovarian, pancreatic or renal cancers, suggesting the gene mutation may be involved in multiple cancer types. Only about 10% of women with an inherited risk of breast or ovarian cancer carry mutations in the genes BRCA1 or BRCA2, which are known to be associated with those diseases. Consequently, some inherited risk of breast and ovarian cancer may stem from mutations in BAP1 genes. According to the authors, it appears likely that other genes, in addition to BAP1, will be found to be associated with elevated risk of mesothelioma.


The researchers first suspected that mutations in the BAP1 gene might underlie mesothelioma in people with a strong family history of the disease after noticing genetic changes in or near other stretches of DNA where the BAP1 gene is located. Looking more closely at two families with unusually high rates of mesothelioma, they saw that every person who had provided a sample and had developed mesothelioma or melanoma of the eye also carried mutations in the BAP1 gene. Further investigation led to sequencing the gene in 26 individuals who had developed mesothelioma but did not have a family history of the disease. Tumors from about 25% of this group carried mutations in the BAP1 gene, and in two cases the mutations were inherited. Both of the individuals with inherited mutations had previously developed melanoma of the eye.


This discovery is a first step in understanding the role of the BAP1 gene and its potential utility when screening for mutations in those at high risk, and also demonstrates that individual genetic makeup can greatly influence susceptibility to mesothelioma. People exposed to dangerous levels of asbestos or erionite, those with a strong family history of mesothelioma, or those who have been previously diagnosed with a rare tumor of the eye known as uveal melanoma, may benefit from this new discovery.


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Gene Replacement Treats Copper Deficiency Disorder in Mice




Copper is used in the formation of red blood cells, and for keeping nervous system tissue, bones, and the immune system healthy. Menkes disease results from a poorly functioning copy of the gene ATP7A. Ordinarily, the gene helps the body process the trace metal copper. In Menkes disease, the gene malfunctions. As a result, copper is not available for proper development. Although the disorder affects the entire body, it is most pronounced in the brain, which requires relatively larger amounts of copper during development than other organs and tissues.


Menkes disease affects 1 out of 50,000 to 100,000 newborns each year, the vast majority of them boys. The disorder varies in severity, depending on the degree to which the gene is disabled. Those with the most poorly functioning copy of the gene fare worst, often dying very early in life. Current treatment consists of daily copper injections until a child is 3 years old. Copper injections can be effective when Menkes disease is detected early and there is some ability to process copper, as in the case of an ATP7A gene with partial function. However, severe and advanced cases generally are not treatable. Most children with the disease die before they reach 3 years of age.


According to a study online in the journal Molecular Therapy (August 2011), gene therapy plus an injection of copper dramatically improved survival in mice with a condition that mimics Menkes disease.


The study was conducted using a strain of mice with a largely disabled copy of ATP7A. In these mice, the ability to transport copper is severely disrupted. The animals do not respond to copper injections alone and typically die within two weeks of birth. Functional ATP7A genes were inserted into the animals’ brains via a harmless virus carrying the gene. Once injected, copies of the virus entered some of the cells in the animals’ brains. The ATP7A gene then began functioning inside these brain cells and increased the ability to process copper.


The study divided the mice into three groups. The first group received copper alone. The second group received the ATP7A-containing virus alone. Mice in both of these groups tended to live two to three days longer than did untreated mice. However, none survived beyond three weeks, the age at which mice typically are weaned from their mothers. The third group of mice received an injection of the ATP7A-containing virus and then, a day later, a dose of copper. On average, these mice survived three times longer than did the untreated mice. Nearly 90% survived to weaning and more than 20% were still alive at 10 months. Results also showed that copper levels were much higher in the brains of mice receiving the treatment of ATP7A plus copper than were copper levels in the brains of the untreated mice. In addition, the brains of the treated mice showed far less damage than those of untreated mice.


The authors explained that the study’s success may have been due to the area of the brain where the ATP7A-carrying viruses were injected. The treatment occurred inside the brain’s ventricles – fluid-filled cavities inside the brain. This fluid is referred to as cerebrospinal fluid, because it bathes the brain and spinal cord. Cerebrospinal fluid is manufactured by specialized cells inside the ventricles, the choroid plexus epithelial cells. When brain tissue from the mice was examined, it was found that the injected ATP7A gene had been incorporated into these cells.


Direct injections of the combined treatment into the brain ventricles were shown to be effective in mice. But direct injections into the brain carry a risk of swelling and infections. For patients with Menkes disease, it would be preferable to find other, less intrusive, ways to deliver the replacement gene. One potential strategy would be to deliver the treatment into the cerebrospinal fluid of the spinal cavity in the lower back, using a common injection procedure known as lumbar puncture.


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Uterine Stem Cells Used to Treat Diabetes in Mice




The endometrium, or uterine lining, is a source of adult stem cells. Normally, these cells generate uterine tissue each month as part of the menstrual cycle. Like other stem cells, however, they can divide to form other kinds of cells.


According to an article published in Molecular Therapy, it was found that stem cells from the human endometrium which were converted into insulin-producing cells and transplanted them into mice, were able to control the animals’ diabetes. The study’s findings suggest the possibility that endometrial stem cells could be used to develop insulin-producing islet cells. These islet cells could then be used to advance the study of islet cells transplantation as a treatment for people with diabetes. According to the authors, if the transplantation of islet cells derived from endometrial cells is perfected, women with diabetes could provide their own endometrial tissue for such a transplant, sidestepping the chance of rejection posed by tissue from another person. Endometrial stem cells are readily available and can be collected easily during a simple outpatient procedure. Endometrial tissue could also be collected after hysterectomy, the surgical removal of the uterus.


The study authors note that such a treatment would be more useful for people with Type 1 diabetes, in which no insulin is produced. The treatment would be less useful for Type 2 diabetes, in which insulin is usually produced, but in which cells have difficulty using the insulin that is available. According to the authors, endometrial tissue samples could be warehoused in a tissue bank, and a large number of samples would make it comparatively easy to find compatible tissue for transplant to women who no longer have a uterus and to men. According to the Centers for Disease Control and Prevention, roughly 600,000 hysterectomies are performed each year in the United States as treatment for a number of disorders and conditions.


For the study, endometrial stem cells were bathed in cultures containing special nutrients and growth factors. Responding to these substances, the endometrial stem cells adopted the characteristics of beta cells, cells of the pancreas that produce insulin. The incubation process took about three weeks. During this time, the endometrial stem cells took on the shape of beta cells and began making proteins typically made by beta cells. The researchers found that some of these cells also produced insulin.


After a meal, the body breaks food down into components like the sugar, glucose. Glucose then circulates in the blood. In response, beta cells release insulin, which allows the body’s cells to take in the circulating glucose. In the study, the mature stem cells were exposed to glucose and it was found that, like typical beta cells, the cultured cells responded by producing insulin. Next, the mature, insulin-making cells were injected into the kidney capsule (membrane surrounding the kidney) of mice having a laboratory-induced form of diabetes. The mice had few working beta cells and very high levels of blood glucose. In mice that did not receive the stem cell therapy, blood sugar levels remained high. Additionally, the mice became lethargic and developed cataracts – both signs of untreated diabetes. In contrast, mice receiving the cell therapy were active and did not develop cataracts. However, the treatment was not entirely effective, as the animals’ blood sugar remained higher than normal. Still, the animals continued to produce some insulin for six weeks, at which time the study ended.

TARGET HEALTH excels in Regulatory Affairs and Public Policy issues. Each week we highlight new information in these challenging areas.



FDA Draft Guidance on Risk-Based Monitoring



FDA has issues a Draft Guidance for Industry entitled: “Oversight of Clinical Investigations – A Risk-Based Approach to Monitoring.“ Target Health wants to congratulate the hard work of the dedicated members of the Clinical Trial Transformation Initiative, under the leadership of Dr. Judith Kramer (Duke University School of Medicine) and Dr. Briggs Morrison (Pfizer). In addition, Target Health is honored that 2 of the references cited in this draft guidance were co-authored by Dr. Jules T. Mitchel, President of Target Health.


The guidance is intended to assist sponsors of clinical investigations in developing risk-based monitoring strategies and plans for investigational studies of medical products, including human drug and biological products, medical devices, and combinations thereof. The overarching goal of this guidance is to enhance human subject protection and the quality of clinical trial data. This guidance is intended to make clear that sponsors can use a variety of approaches to fulfill their responsibilities related to monitoring investigator conduct and the progress of investigational new drug (IND) or investigational device exemption (IDE) studies. This guidance describes strategies for monitoring activities that reflect a modern, risk-based approach that focuses on critical study parameters and relies on a combination of monitoring activities to oversee a study effectively. For example, the guidance specifically encourages greater use of centralized monitoring methods where appropriate.


Congratulations to FDA on encouraging the Industry to run clinical trials in a more productive manner. This is an excellent guidance which will permit the Industry to replace labor-intensive, minimally productive procedures with currently available technologies and approaches to improve the monitoring of the quality of clinical trials and the safety of patients participating in clinical trials.


Specifically, the following statements within the guidance document are critical:


  1. Quality is a systems property that must be built into an enterprise and cannot be achieved by oversight or monitoring alone.
  2. FDA will ensure that the bioresearch monitoring compliance program guidance manuals (CPGMs) 176 for sponsors, CROs, and monitors (CPGM 78.810) 24 and for clinical investigators and sponsor-investigators (CPGM 78.811)25 are compatible with the approaches described in this guidance
  3. Many other factors contribute to the quality and integrity of a clinical investigation. The most important tool for ensuring human subject protection and high-quality data is a well- designed and articulated protocol. A poorly designed or ambiguous protocol or case report form (CRF) may introduce systemic errors that can render a clinical investigation unreliable despite rigorous monitoring. Study-specific training of investigators, other site staff, and monitors also contributes significantly to study quality

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, execution of Clinical Trials, Project Management, Biostatistics and Data Management, EDC utilizing Target e*CRF®, 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*CTMS™

3) Target Document®

4) Target Encoder®

5) Target Newsletter®

6) Target e*CTR™ (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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