Director of Operations

 

Target Health is looking for a Director of Operations to work closely with the company’s President to optimize operations and to assist in client interactions. The candidate must know the pharma industry from top to bottom and must know about software systems. If you know anyone who might be interested, send the resume and a cover note to Mr. Neil Lassalle.

Target Document as an Electronic Trial Master File

 

Target Document®, Target Health’s premier document management system, allows for companies to run their clinical operation Trial Master File (TMF) totally paperlessly. The system comes with standard e*TMF templates which are fully configurable, routing of documents for electronic signatures, document renewal notifications, advanced user management, session and system logs and many more features. Please take a look at our whitepaper on how you can save a bundle.

 

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 at: www.targethealth.com

 

World Malaria Day is Monday 25th April

Although malaria has been virtually eradicated in the US and other regions with temperate climates, it continues to affect hundreds of people in the US every year. The Centers for Disease Control and Prevention (CDC) estimates 1,200 cases of malaria are diagnosed each year. People who live in the US typically get malaria during trips to malaria-endemic areas of the world.



Malaria is a disease caused by a parasite that lives part of its life in humans and part in the mosquitoe. Malaria remains one of the major killers of 1) ___ worldwide, threatening the lives of more than one-third of the world’s population. It thrives in the tropical areas of Asia, Africa, and Central and South America, where each year there are 350 to 500 million cases. Sadly, more than 1 million of its victims, mostly young children, 2) ___ yearly.

 

Only female mosquitoes feed on blood while 3) ___ mosquitoes feed on plant nectar, thus males do not transmit the disease. The females of the Anopheles genus of mosquito prefer to feed at night. Malaria parasites are rarely transmitted by blood transfusions.

 

A mosquito infects a person by taking a 4) ___ meal. Malaria develops via two phases: an exoerythrocytic and an erythrocytic phase. The exoerythrocytic phase involves infection of the hepatic system, or 5) ___, whereas the erythrocytic phase involves infection of the erythrocytes, or red blood cells. When an infected mosquito pierces a person’s skin to take a blood meal, sporozoites in the mosquito’s saliva enter the bloodstream and migrate to the liver. Within minutes of being introduced into the human host, the sporozoites infect hepatocytes, multiplying asexually and asymptomatically for a period of 8-30 days. Once in the liver, these organisms differentiate to yield thousands of merozoites, which, following rupture of their host cells, escape into the blood and infect red blood cells, thus beginning the erythrocytic stage of the life 6) ___. The parasite escapes from the liver undetected by wrapping itself in the cell membrane of the infected host liver cell. Within the red blood cells, the parasites multiply further, again asexually, periodically breaking out of their hosts to invade fresh red blood cells. Several such amplification cycles occur. Thus, classical descriptions of waves of fever arise from simultaneous waves of merozoites escaping and infecting red blood cells.

 

Some P. vivax and P. ovale sporozoites do not immediately develop into exoerythrocytic-phase merozoites, but instead produce hypnozoites that remain dormant for periods ranging from several months (6-12 months is typical) to as long as three 7) ___. After a period of dormancy, they reactivate “stickiness“ as the main factor giving rise to hemorrhagic complications of malaria. High endothelial venules (the smallest branches of the circulatory system) can be blocked by the attachment of masses of these infected red blood cells. The blockage of these vessels causes symptoms, such as in placental and cerebral malaria. In cerebral malaria the sequestrated red blood cells can breach the blood brain barrier possibly leading to coma. Although the white blood cell surface adhesive proteins are exposed to the immune system, they do not serve as good immune targets, because of their extreme diversity. There are at least 60 variations of the 8) ___ within a single parasite and effectively limitless versions within parasite populations. The parasite switches between a broad repertoire of PfEMP17 surface proteins, thus staying one step ahead of the pursuing immune system.

 

Some merozoites turn into male and female gametocytes. Since the gametocytes are formed in the blood of the vertebrate host, the vertebrate host is the definitive host of the disease. If a mosquito pierces the skin of an infected person, it potentially picks up gametocytes within the blood. Fertilization of the parasite occurs in the mosquito’s gut. New sporozoites develop and travel to the mosquito’s salivary 9) ___, completing the cycle.

 

Pregnant women are especially attractive to the mosquitoes, and malaria in pregnant women is an important cause of stillbirths, infant mortality and low birth weight. The parasite is relatively protected from attack by the body’s immune system because for most of its human life cycle it resides within the liver and blood cells and is relatively invisible to immune surveillance. However, circulating infected blood cells are destroyed in the spleen. To avoid this fate, the P. falciparum parasite displays adhesive proteins on the surface of the infected blood cells, causing the blood cells to stick to the walls of small blood vessels, thereby sequestering the parasite from passage through the general circulation and the 10) ___.

 

Many biological and environmental factors shape the character of malaria in a given location. Nearly all the people who live in endemic areas are exposed to infection repeatedly. Those who survive 11) ___ in childhood gradually build up some immunity. They may carry the infection, serving as reservoirs for transmission by mosquitoes without developing severe disease. In other areas, where the infection rate is low, people do not develop immunity because they rarely are exposed to the disease. This makes them more susceptible to the ravages of an epidemic.

 

An epidemic can occur when conditions, such as rainfall, allow the mosquito population to increase suddenly. Climate affects both parasites and 12) ___. Mosquitoes cannot survive in low humidity. Rainfall expands breeding grounds, and in many tropical areas, malaria cases increase during the rainy season. Mosquitoes must live long enough for the parasite to complete its development within them. Therefore, environmental factors that affect mosquito survival can influence malaria incidence.

Quinine was used historically, as a treatment for malaria; however, the development of more effective alternatives such as quinacrine, chloroquine, and primaquine in the 20th century reduced its use. Today, quinine is not generally used for prophylaxis. The use of prophylactic 13) ___ where malaria-bearing mosquitoes are present may encourage the development of partial immunity.

 

ANSWERS: 1) humans; 2) die; 3) male; 4) blood; 5) liver; 6) cycle; 7) years; 8) protein; 9) gland; 10) spleen; 11) malaria; 12) mosquitoes; 13) drugs

 

 

 

Malaria

Dr. Probert’s Malarial Remedy, “Will cure bilious fever, liver complaint & c.“, c.1881, New York



Malaria has infected humans for over 50,000 years, and Plasmodium may have been a human pathogen for the entire history of the species. Close relatives of the human malaria parasites remain common in chimpanzees. Some new evidence suggests that the most virulent strain of human malaria may have originated in gorillas.

 

References to the unique periodic fevers of malaria are found throughout recorded history, beginning in 2700 BCE in China. Malaria may have contributed to the decline of the Roman Empire, and was so pervasive in Rome that it was known as the “Roman fever.“

 

The early Egyptians wrote about it on papyrus, and the famous Greek physician Hippocrates described malaria in detail. Malaria devastated invaders of the Roman Empire. In ancient Rome, as in other temperate climates, malaria lurked in marshes and swamps. People blamed the unhealthiness in these areas on rot and decay that wafted out on the foul air. Hence, the name is derived from the Italian, “mal aria,“ or bad air. In 1880, the French scientist Alphonse Laveran discovered the real cause of malaria, the single-celled Plasmodium parasite. Almost 20 years later, scientists working in India and Italy discovered that Anopheles mosquitoes are responsible for transmitting malaria.

Historically, in the United States malaria, then commonly known as “fever and ague,“ took a toll on early settlers. It is believed that the incidence of malaria in this country peaked around 1875, but by 1914, there were still more than 600,000 new cases. Malaria has been a significant factor in virtually all of the military campaigns involving the United States. In World War II and the Vietnam War, more personnel time was lost due to malaria than to bullets. Malaria was the most important health hazard encountered by U.S. troops in the South Pacific during World War II, where about 500,000 men were infected. According to Joseph Patrick Byrne, “Sixty thousand American soldiers died of malaria during the African and South Pacific campaigns.“

 

The discovery that malaria was transmitted by mosquitoes unleashed a flurry of ambitious public health measures designed to stamp out malaria. These measures were targeted at both the larval stages (which thrive in still waters, such as swamps) and adult stages of the insect. In some areas, such as the southern United States, draining swamps and changing the way land was used was somewhat successful in eliminating mosquitoes. The first effective treatment for malaria came from the bark of cinchona tree, which contains quinine. This tree grows on the slopes of the Andes, mainly in Peru. The indigenous peoples of Peru made a tincture of cinchona to control malaria. The Jesuits noted the efficacy of the practice and introduced the treatment to Europe during the 1640s, where it was rapidly accepted. It was not until 1820 that the active ingredient, quinine, was extracted from the bark, isolated and named by the French chemists Pierre Joseph Pelletier and Joseph Bienaime Caventou. In the 20th century, chloroquine replaced quinine as treatment of both uncomplicated and severe falciparum malaria until resistance supervened. Artemisinins, discovered by Chinese scientists in the 1970s, are now recommended treatment for falciparum malaria, administered in combination with other antimalarials.

 

The pace of the battle against malaria, accelerated rapidly when the insecticide DDT and the drug chloroquine were introduced during World War II. DDT was remarkably effective and could be sprayed on the walls of houses where adult Anopheles mosquitoes rested after feeding. In the mid-1950s, the World Health Organization (WHO) launched a massive worldwide campaign to eliminate malaria. At the beginning, the WHO program, which combined insecticide spraying and drug treatment, had many successes, some spectacular. In some areas, malaria was conquered completely, benefiting more than 600 million people, and was sharply curbed in the homelands of 300 million others. However, some stumbling blocks were administrative, others financial. Even worse, nature intervened. More and more strains of Anopheles mosquitoes developed resistance to DDT and other insecticides, and the environmental impact of DDT was recognized. Meanwhile, the Plasmodium parasite became resistant to chloroquine, the mainstay of antimalarial drug treatment in humans.

 

 

Veterans Affairs Initiative Prevents Methicillin-Resistant Staphylococcus aureus Infections

The following article explains clearly why we need to focus on optimizing healthcare reform rather than focusing on health insurance reform. There are so many areas where we can improve patient care which will clearly result in reduced costs.

 

Health care-associated infections with methicillin-resistant Staphylococcus aureus (MRSA) have been an increasing concern in Veterans Affairs (VA) hospitals. As a result, a study published in the New England of Medicine (2011; 364:1419-1430), was initiated in acute care VA hospitals nationwide in an effort to decrease health care-associated infections with MRSA. The study used the concept of a “MRSA bundle“ intervention. The bundle consisted of universal nasal surveillance for MRSA, contact precautions for patients colonized or infected with MRSA, hand hygiene, and a change in the institutional culture whereby infection control would become the responsibility of everyone who had contact with patients. Each month, personnel at each facility entered into a central database aggregate data on adherence to surveillance practice, the prevalence of MRSA colonization or infection, and health care-associated transmissions of and infections with MRSA.

 

From October 2007, when the bundle was fully implemented, through June 2010, there were 1,934,598 admissions to or transfers or discharges from intensive care units (ICUs) and non-ICUs (ICUs, 365,139; non-ICUs, 1,569,459) and 8,318,675 patient-days (ICUs, 1,312,840; and non-ICUs, 7,005,835).

 

During this same period, the percentage of patients who were screened at admission increased from 82% to 96%, and the percentage who were screened at transfer or discharge increased from 72% to 93%. The mean (+SD) prevalence of MRSA colonization or infection at the time of hospital admission was 13.6+3.7%. The rates of health care-associated MRSA infections in ICUs had not changed in the 2 years before October 2007 (P=0.50 for trend) but declined with implementation of the bundle, from 1.64 infections per 1000 patient-days in October 2007 to 0.62 per 1000 patient-days in June 2010, a decrease of 62% (P<0.001 for trend). During this same period, the rates of health care-associated MRSA infections in non-ICUs fell from 0.47 per 1000 patient-days to 0.26 per 1000 patient-days, a decrease of 45% (P<0.001 for trend).

According to the authors, a program of universal surveillance, contact precautions, hand hygiene, and institutional culture change was associated with a decrease in health care-associated transmissions of and infections with MRSA in a large health care system.

 

Alzheimer’s Diagnostic Guidelines Updated

 

 

For the first time in 27 years, clinical diagnostic criteria for Alzheimer’s disease (AD) dementia have been revised, and research guidelines for earlier stages of the disease have been characterized to reflect a deeper understanding of the disorder. The National Institute on Aging/Alzheimer’s Association Diagnostic Guidelines for Alzheimer’s Disease outline some new approaches for clinicians and provides scientists with more advanced guidelines for moving forward with research on diagnosis and treatments. They mark a major change in how experts think about and study Alzheimer’s disease. Development of the new guidelines was led by the National Institutes of Health and the Alzheimer’s Association.

 

The original criteria were the first to address the disease and described only later stages, when symptoms of dementia are already evident. The updated guidelines cover the full spectrum of the disease as it gradually changes over many years. They describe the earliest preclinical stages of the disease, mild cognitive impairment, and dementia due to AD’s pathology. Importantly, the guidelines now address the use of imaging and biomarkers in blood and spinal fluid that may help determine whether changes in the brain and those in body fluids are due to AD. Biomarkers are increasingly employed in the research setting to detect onset of the disease and to track progression, but cannot yet be used routinely in clinical diagnosis without further testing and validation.

 

The new guidelines appear online April 19, 2011 in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association. They were developed by expert panels convened last year by the National Institute on Aging (NIA), part of the NIH, and the Alzheimer’s Association. Preliminary recommendations were announced at the Association’s International Conference on Alzheimer’s Disease in July 2010, followed by a comment period.

 

The original 1984 clinical criteria for AD, reflecting the limited knowledge of the day, defined AD as having a single stage, dementia, and based diagnosis solely on clinical symptoms. It assumed that people free of dementia symptoms were disease-free. Diagnosis was confirmed only at autopsy, when the hallmarks of the disease, abnormal amounts of amyloid proteins forming plaques and tau proteins forming tangles, were found in the brain. Since then, research has determined that AD may cause changes in the brain a decade or more before symptoms appear and that symptoms do not always directly relate to abnormal changes in the brain caused by AD. For example, some older people are found to have abnormal levels of amyloid plaques in the brain at autopsy yet never showed signs of dementia during life. It also appears that amyloid deposits begin early in the disease process but that tangle formation and loss of neurons occur later and may accelerate just before clinical symptoms appear.

 

To reflect what has been learned, the National Institute on Aging/Alzheimer’s Association Diagnostic Guidelines for Alzheimer’s Disease cover three distinct stages of Alzheimer’s disease:

 

— Preclinical — The preclinical stage, for which the guidelines only apply in a research setting, describes a phase in which brain changes, including amyloid buildup and other early nerve cell changes, may already be in process. At this point, significant clinical symptoms are not yet evident. In some people, amyloid buildup can be detected with positron emission tomography (PET) scans and cerebrospinal fluid (CSF) analysis, but it is unknown what the risk for progression to AD is for these individuals. However, use of these imaging and biomarker tests at this stage are recommended only for research. These biomarkers are still being developed and standardized and are not ready for use by clinicians in general practice.

 

— Mild Cognitive Impairment (MCI) — The guidelines for the MCI stage are also largely for research, although they clarify existing guidelines for MCI for use in a clinical setting. The MCI stage is marked by symptoms of memory problems, enough to be noticed and measured, but not compromising a person’s independence. People with MCI may or may not progress to AD dementia. Researchers will particularly focus on standardizing biomarkers for amyloid and for other possible signs of injury to the brain. Currently, biomarkers include elevated levels of tau or decreased levels of beta-amyloid in the CSF, reduced glucose uptake in the brain as determined by PET, and atrophy of certain areas of the brain as seen with structural magnetic resonance imaging (MRI). These tests will be used primarily by researchers, but may be applied in specialized clinical settings to supplement standard clinical tests to help determine possible causes of MCI symptoms.

 

— Alzheimer’s Dementia — These criteria apply to the final stage of the disease, and are most relevant for doctors and patients. They outline ways clinicians should approach evaluating causes and progression of cognitive decline. The guidelines also expand the concept of AD dementia beyond memory loss as its most central characteristic. A decline in other aspects of cognition, such as word-finding, vision/spatial issues, and impaired reasoning or judgment may be the first symptom to be noticed. At this stage, biomarker test results may be used in some cases to increase or decrease the level of certainty about a diagnosis of AD dementia and to distinguish AD dementia from other dementias, even as the validity of such tests is still under study for application and value in everyday clinical practice.

 

The panels purposefully left the guidelines flexible to allow for changes that could come from emerging technologies and advances in understanding of biomarkers and the disease process itself.

 

GENETICS

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Common Genetic Variant Linked To Pulmonary Fibrosis Risk

A common genetic variant has been identified which is associated with substantially increased risk of developing pulmonary fibrosis, a debilitating and life-threatening lung condition. The genetic variant is found in a region of DNA thought to regulate the production of an important mucus-forming protein. This genetic variant near the mucin 5B gene, termed rs35705950, is both fairly common and a risk factor for idiopathic pulmonary fibrosis (IPF) and familial interstitial pneumonia (FIP). IPF and FIP are two related lung diseases that produce progressive, irreversible, and currently incurable scarring of the lungs, which is called fibrosis.

 

The study, published in the New England Journal of Medicine (2011; 364:1503-1512), compared the gene sequences of 575 individuals affected by IPF (492) or FIP (83) as well as 322 healthy people. Results showed that more than half of the IPF/FIP study participants have at least one copy of the variant, compared to one in six healthy controls who have the variant. Those with one copy have approximately five- to eightfold increased odds of developing fibrosis in their lungs, compared to those without the genetic variant. Individuals who have two copies of the variant have approximately twentyfold greater odds of developing fibrosis in their lungs. According to the authors, the study highlights how an investment in genomics can pay off and that we are now one step closer to understanding these serious and mysterious diseases that affect over 100,000 Americans. However, the authors cautioned that this variant alone cannot predict disease risk for an individual. Many people who have the variant still have healthy lungs, so genetic testing for rs35705950 alone is unlikely to help doctors to diagnose their patients. As yet unknown modifying genetic and/or environmental factors are likely to affect development of disease in persons who possess the genetic variant.

 

Since the risk of IPF or FIP in the general population is low, the absolute risk — the likelihood that an individual will have the condition — is still low, even for those with the variant. Nevertheless, this discovery has immediate importance for scientists who study pulmonary fibrosis, since it may point to the root causes of IPF and FIP and to new ways to prevent and manage these conditions. The genetic alteration occurs in a region called the promoter, near the mucin 5B gene. The promoter region regulates gene expression, and the identified variant ramps up the production of mucin 5B protein, causing normal lungs to produce over 35 times as much of this mucus-forming protein compared to controls.

 

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

 

FDA Approves New Medical Device for Glioblastoma Multiforme

 

 

Brain tumors are the growth of abnormal cells in the brain tissue. According to the National Cancer Institute, each year about 19,000 people in the US are diagnosed with primary brain cancers. In 2010, there were 13,140 deaths from brain and other nervous system cancers in the US. Glioblastoma multiforme (GBM) is the most common primary brain cancer. The brain tumor is highly resistant to standard treatments such as surgery, radiation and chemotherapy.

The FDA has approved the NovoTTF-100A System, a new device to treat adults with GBM that recurs or progresses after receiving chemotherapy and radiation therapy. When using the NovoTTF-100A System, a health care professional places electrodes on the surface of the patient’s scalp to deliver low-intensity, changing electrical fields called “tumor treatment fields“ (TTFs) to the tumor site. The unique shape and electrical characteristics of dividing tumor cells make them susceptible to damage when exposed to TTF, which could stop tumor growth.

 

The device is portable and can be powered with batteries or plugged into an electrical outlet. Patients can use the device at home, allowing them to continue their normal daily activities. The FDA based its approval of the NovoTTF-100A System on results from a single international clinical study in 237 patients with recurrent GBM or with GBM that hadn’t responded to traditional therapy. Patients in the study were randomly assigned to receive either the NovoTTF-100A System or chemotherapy treatment.

 

The trial demonstrated that patients treated with the NovoTTF alone achieved a comparable overall survival time to patients treated with the physician’s choice of the best chemotherapy. Patients treated with the NovoTTF also had higher rates of progression free survival at six months (PFS6) and higher tumor response rates (RR) compared to chemotherapy treated patients in the trial (PFS6 of 21% vs. 15%).

 

NovoTTF treated patients reported better quality of life scores and fewer side effects during the trial compared to patients treated with chemotherapy. The NovoTTF’s most commonly reported side effect was a mild-to-moderate rash beneath the electrodes. The study showed comparable overall survival rates between patients treated with the NovoTTF-100A System and those who underwent chemotherapy.

 

Patients treated with the NovoTTF-100A System experienced a slightly higher incidence of neurological side effects including convulsions and headaches compared to patients receiving chemotherapy. However, they did not experience the significant side effects associated with chemotherapy, including nausea, anemia, fatigue and serious infections.

 

A survey of patients in the study suggested an improved quality of life in the NovoTTF-100A recurrent GBM patients compared to patients receiving chemotherapy.

 

Patients should not use the NovoTTF-100A System if they have an implanted medical device or a skull defect, or have a known sensitivity to conductive hydrogels, such as those used with electrocardiograms. The NovoTTF-100A System is not intended to be used in combination with other cancer treatment. The device should only be used after other treatments have failed.

 

The NovoTTF-100A System is made by Novocure of Portsmouth, N.H.

 

For more information about our expertise in Medical Affairs, contact Dr. Mark L. Horn. For 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, 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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