A Must Webinar: eSource and the Paperless Clinical Trial



Target Health is pleased to announce that Dr. Jules T. Mitchel will be running a Webinar, sponsored by FDANEWS, on the topic of “eSource and the Paperless Clinical Trial.“ The 90 minute Webinar will take place this Tuesday at 1:30.


Finally, in the clinical trial arena, the the R. Buckminster Fuller mantra of “doing more with less“ has arrived. Less paper equals more productivity, reduced time to the market and a greener world. If you’re looking to decrease onsite monitoring, decrease data entry transcription errors, decrease time to database lock, etc. now is your chance to learn how. Here are just a few of the specifics of the Webinar:


  • Source records: What they are, and the FDA’s perspective
  • Complying with FDA’s proposal for direct data entry
  • Paper backups for electronic records – the risks and the rewards
  • Impact of direct data entry on clinical research and data management
  • Paradigm shift: Product development and direct data entry
  • Impact of companies providing monitoring, data management and EDC services
  • And much more

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,

Over Half of Alzheimer’s Cases May Be Preventable



Scientists can see the terrible effects of Alzheimer’s disease (AD) when they look at brain tissue under the microscope. AD tissue has many fewer 1) ___ cells and synapses than a healthy brain. Plaques, abnormal clusters of 2) ___ fragments, build up between nerve cells. Dead and dying nerve cells contain tangles, which are made up of twisted strands of another protein.


Plaques form when protein pieces called beta-amyloid  clump together. Beta-amyloid comes from a larger protein found in the fatty membrane surrounding nerve cells. Beta-amyloid is chemically “sticky“ and gradually builds up into plaques. The most damaging form of beta-amyloid may be groups of a few pieces rather than the plaques themselves. The small clumps may block cell-to-cell signaling at 3) ___. They may also activate immune system cells that trigger inflammation and devour disabled cells



Tangles destroy a vital cell transport system made of proteins. This electron microscope picture shows a cell with some healthy areas and other areas where 4) ___ are forming.



Over half of all AD cases could potentially be prevented through lifestyle changes and treatment or prevention of chronic medical conditions, according to a study led by Deborah Barnes, PhD, a mental health researcher at the San Francisco VA Medical Center. Analyzing data from studies around the world involving hundreds of thousands of participants, Barnes concluded that worldwide, the biggest modifiable risk factors for AD are, in descending order of magnitude, low 5) ___, smoking, physical inactivity, depression, mid-life hypertension, diabetes and mid-life obesity. In the United States, Barnes found that the biggest modifiable risk factors are physical 6) ___, depression, smoking, mid-life hypertension, mid-life obesity, low education and diabetes. Together, these risk factors are associated with up to 51%of AD cases worldwide (17.2 million cases) and up to 54% of Alzheimer’s cases in the United States (2.9 million cases), according to Barnes.


“What’s exciting is that this suggests that some very simple lifestyle changes, such as increasing 7) ___ activity and quitting smoking, could have a tremendous impact on preventing AD and other dementias in the US and worldwide,“ said Barnes, who is also an associate professor of psychiatry at the University of California, San Francisco. The study results were presented at the 2011 meeting of the Alzheimer’s Association International Conference on Alzheimer’s Disease in Paris, France, and published online on July 19, 2011 in Lancet Neurology.


Barnes cautioned that her conclusions are based on the assumption that there is a 8) ___ association between each risk factor and AD. “We are assuming that when you change the risk factor, then you change the 9) ___,“ Barnes said. “What we need to do now is figure out whether that assumption is correct.“ Senior investigator Kristine Yaffe, MD, chief of geriatric psychiatry at SFVAMC, noted that the number of people with Alzheimer’s disease is expected to 10) ___ over the next 40 years. “It would be extremely significant if we could find out how to prevent even some of those cases,“ said Yaffe, who is also a professor of psychiatry, neurology and epidemiology at UCSF.


ANSWERS 1) nerve; 2) protein; 3) synapses; 4) tangles; 5) education; 6) inactivity; 7) physical; 8) causal; 9) risk; 10) triple

Malaria – Part 2





Malaria is a mosquito-borne infectious disease caused by eukaryotic protists of the genus Plasmodium (see illustration above). Malaria is widespread in tropical and subtropical regions, including much of Sub-Saharan Africa, Asia and the Americas. Malaria is prevalent in these regions because of the significant amounts of rainfall and consistent high temperatures.


The genus Plasmodium was described in 1885 by Ettore Marchia. Of the over 200 known species of Plasmodium, at least 11 species infect humans. Other species infect other animals, including monkeys, rodents, birds, and reptiles. The parasite always has two hosts in its life cycle: a mosquito vector and a vertebrate host.


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 Bienaim? Caventou.


The cause of Malaria is a protozoan, discovered in 1880 by Charles Louis Alphonse Lavern. While Lavern was working in the military hospital in Constantine, Algeria, he observed the parasites in a blood smear taken from a patient who had just died of malaria.


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



Laveran proposed that malaria is caused by this organism, the first time a protist was identified as causing disease. For this and later discoveries, he was awarded the 1907 Nobel Prize for Physiology or Medicine. In April 1894, a Scottish physician Sir Ronald Ross started a 4-year collaboration with Sir Patrick Manson which culminated in 1898 when Ross, who was working in the Presidency General Hospital in Calcutta, proved the complete life-cycle of the malaria parasite in mosquitoes. He did this by showing that certain mosquito species transmit malaria to birds by isolating malaria parasites from the salivary glands of mosquitoes that had fed on infected birds. For this work, Ross received the 1902 Nobel Prize in Medicine.


In the 20th century, chloroquine replaced quinine as treatment of both uncomplicated and severe falciparum malaria until resistance supervened. 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.“



Mosaic Analysis with Double Markers Reveals Tumor Cell of Origin in Glioma


Malignant glioma is diagnosed in 10,000 Americans annually, with most patients dying within two years. Victims have included U.S. Sen. Ted Kennedy (2009), pianist George Gershwin (1937), marine biologist Thor Heyerdahl (2002) and film critic Gene Siskel (1999). An autopsy on Charles Whitman, who killed 13 during a shooting rampage at the University of Texas in 1966, uncovered a glioma tumor intruding into areas of the brain related to emotion and aggression.


Cancer cell of origin is difficult to identify by analyzing cells within terminal stage tumors, whose identity could be concealed by the acquired plasticity. Thus, an ideal approach to identify the cell of origin is to analyze proliferative abnormalities in distinct lineages prior to malignancy. According to an article published in the journal Cell (2011;146:209-221), a mosaic analysis with double markers (MADM) was used to model gliomagenesis by initiating concurrent p53/Nf1 mutations sporadically in neural stem cells (NSCs) in mice. The essence of MADM is its unambiguous labeling of mutant cells with green fluorescent protein, which allows for probing into pre-clinical, tumor-initiating stages that are inaccessible using conventional tools.


Study results showed that MADM-based lineage tracing revealed significant aberrant growth prior to malignancy only in oligodendrocyte precursor cells (OPCs), but not in any other NSC-derived lineages or NSCs themselves. Upon tumor formation, phenotypic and transcriptome analyses of tumor cells revealed salient OPC features. Finally, introducing the same p53/Nf1 mutations directly into OPCs consistently led to gliomagenesis. The findings suggest OPCs as the cell of origin in this model, even when initial mutations occur in NSCs, and highlight the importance of analyzing premalignant stages to identify the cancer cell of origin.


Further analyses of all cell lineages derived from neural stem cells also demonstrated that OPCs are the cell of origin since mutant green OPCs over-populate their normal red counterparts by 130-fold before any visible signs of tumor can be detected. To confirm that OPCs have intrinsic ability independent of the mutation-passing process from NSCs, the study also introduced p53 and NF1 mutations directly into OPCs.


According to the authors, studying cancer in this way should not only lead to molecular diagnostics to detect the earliest emergence of any cancers, but also allow the understanding the molecular mechanisms by which initial mutant cells progressively gain advantages over normal cells. The authors added that this type of knowledge should eventually enable the ability to increase the efficacy of cancer treatment.

Zinc Sparks Fly From Egg Within Minutes of Fertilization





According to an article published in ACS Chemical Biology (2011;6:716-723), it has been reported that at fertilization, a massive release of the metal zinc appears to set the fertilized egg cell on the path to dividing and growing into an embryo. The authors referred to the zinc discharge and accompanying light flash as zinc sparks. The zinc discharge followed the egg cell’s steady accumulation of zinc atoms in the developmental stages before fertilization. The study documented the discharge by bathing the eggs in a solution that gives off light when exposed to zinc. The authors suggest that zinc acts as a switch, turning off the process of cell division while the egg matures and turning it on again after fertilization.


In the study, the researchers observed egg cells from mice and from monkeys. To conduct the study, the authors devised a microscope that would allow them to view the concentration and distribution of zinc atoms in individual cells. With the aid of the chemical that gives off light when exposed to zinc, the first zinc sparks were documented 20 minutes after fertilization. Most fertilized eggs released two or three rounds of sparks, but as few as one and as many as five were observed within the first two hours after fertilization. The sparks flared every 10 minutes, on average.


Previous research had shown that fertilization triggers cyclical changes in the level of calcium in the egg cell. The researchers noted that the zinc sparks always occurred after a peak in calcium levels inside the cell.


According to the authors, the number, timing and intensity of these sparks could provide important information about the quality of the egg and will be an important area for future research. The authors added that it may also be worth investigating whether the amount of zinc in a woman’s diet plays a role in fertility.


Additional experiments helped confirm a role for zinc in the fertilization process. Typically, once the egg is released from the ovary, it must get rid of excess chromosomes in two stages as it prepares to fuse with the sperm. The team’s earlier research showed that the early accumulation of zinc is essential for properly completing the first stage. The latest results suggest that zinc may act as a brake in between these stages, as the egg awaits fertilization. If the cell is fertilized, the zinc release appears to lift the brake. The cell discards its excess genetic material and begins to divide. The study also showed that even unfertilized eggs would start to divide if zinc levels were artificially reduced, mimicking release. In addition, when fertilized cells were forced to take on additional zinc, the process was reversed.


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Height and Cancer Incidence in the Million Women Study: Prospective Cohort, and Meta-Analysis of Prospective Studies of Height and Total Cancer Risk


Epidemiological studies have shown that taller people are at increased risk of cancer, but it is unclear if height-associated risks vary by cancer site, or by other factors such as smoking and socioeconomic status. As a result, a study published in The Lancet Oncology, Early Online Publication (21 July 2011), was performed to investigate these associations in a large UK prospective cohort of women.


For the study, information on height and other factors relevant for cancer was obtained between 1996 and 2001 for middle-aged women without previous cancer who were followed up for cancer incidence. The authors used Cox regression models to calculate adjusted relative risks (RRs) per 10 cm increase in measured height for total incident cancer and for 17 specific cancer sites, taking attained age as the underlying time variable. The authors also performed a meta-analysis of published results from prospective studies of total cancer risk in relation to height.


A total of 1,297,124 women were followed up for a total of 11.7 million person-years (median 9.4 years per woman), during which time 97,376 incident cancers occurred. The RR for total cancer was of 1.16 (p<0.0001) for every 10 cm increase in height. Risk increased for 15 of the 17 cancer sites assessed, and was statistically significant for ten sites: colon (RR 1.25), rectum (1.14), malignant melanoma (1.32), breast (1.17), endometrium (1.19), ovary (1.17), kidney (1.29), CNS (1.20), non-Hodgkin lymphoma (1.21), and leukemia (1.26).


The increase in total cancer RR per 10 cm increase in height did not vary significantly by socioeconomic status or by ten other personal characteristics, but was significantly lower in current than in never smokers (p<0.0001). In current smokers, smoking-related cancers were not as strongly related to height as were other cancers (RR per 10 cm increase in height 1.05, and 1.17, respectively; p=0.0004). In a meta-analysis including the present study and ten other prospective studies, height-associated RRs for total cancer showed little variation across Europe, North America, Australasia, and Asia.


According to the authors, cancer incidence increases with increasing adult height for most cancer sites and that the relation between height and total cancer RR is similar in different populations.

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



FDA Outlines Oversight of Mobile Medical Applications



Today, mobile medical applications or “mobile medical apps,“ include a variety of functions, ranging from monitoring calorie intake, helping people maintain a healthy weight, and allowing doctors to view a patient’s radiology images on their mobile communications device. According to Research2Guidance 2010, 500 million smartphone users worldwide will be using a health care application by 2015.


The FDA announced that it is seeking input on its proposed oversight approach for certain mobile applications specific to medicine or health care called mobile medical applications (“apps“) that are designed for use on smartphones and other mobile computing devices. This approach encourages the development of new apps, focuses only on a select group of applications and will not regulate the sale or general consumer use of smartphones or tablets.


“The use of mobile medical apps on smart phones and tablets is revolutionizing health care delivery,“ said Jeffrey Shuren, M.D., J.D., director of the FDA’s Center for Devices and Radiological Health. “Our draft approach calls for oversight of only those mobile medical apps that present the greatest risk to patients when they don’t work as intended.“


The agency’s draft guidance defines a small subset of mobile medical apps that impact or may impact the performance or functionality of currently regulated medical devices. This subset includes mobile medical apps that:


  • are used as an accessory to medical device already regulated by the FDA (e.g., an application that allows a health care professional to make a specific diagnosis by viewing a medical image from a picture archiving and communication system (PACS) on a smartphone or a mobile tablet); or


  • transform a mobile communications device into a regulated medical device by using attachments, sensors or other devices (e.g., an application that turns a smartphone into an ECG machine to detect abnormal heart rhythms or determine if a patient is experiencing a heart attack).


The agency is seeking public input on this approach. Once posted, comments can be submitted for 90 days online or in writing to: Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852. The FDA will update the guidance based on feedback received. For more information, go to:





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.
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2) Target e*CTMS™

3) Target Document®

4) Target Encoder®

5) Target Newsletter®

6) Target e*CTR™ (electronic medical record for clinical trials).
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