New Book Entitled Clinical Research in Oral Health

Target Health is very pleased to announce the publication of a new textbook entitled Clinical Research in Oral Health, edited by William V. Giannobile, Brian A. Burt and Robert J. Genco. Two of the book chapters are co-authored by Dr. Jules T. Mitchel of Target Health. The chapters are: Data Management in Oral Health Research (Bruce A. Dye and Jules T. Mitchel), and Initial Clinical Trials Allow Assessment of Safety, Dosing and Preliminary Efficacy Prior to Large Randomized Controlled Pivotal Studies (Jules T. Mitchel, Glen Park, Mark Citron, Russ Pagano, Leslie Wisner-Lynch, Samuel E. Lynch).

Clinical Research in Oral Health surveys the essentials of clinical research in oral health, anchoring these principles within the specific context of the oral health arena. Addressing research questions exclusively applicable to dentistry and oral health, the book thoroughly illustrates the principles and practice of oral health clinical research. Clinical Research in Oral Health also clarifies the framework of regulatory issues and presents emerging concepts in clinical translation, relating the research principles to clinical improvement.

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, and if you like the weekly newsletter, ON TARGET, you'll love the Blog.

Critical Enzyme in Healthy Heart Function Identified

Scientists are reporting the first-ever data to show that the 1) ___ calcineurin is critical in controlling normal development and function of heart cells, and that loss of the protein leads to heart problems and death in genetically modified mice. To be published Feb. 26 in the Journal of Biological Chemistry as the paper of the week, and posted online Feb. 19, the research was led by scientists at Cincinnati Children's Hospital Medical Center and the Howard Hughes Medical Institute. The study demonstrated that calcineurin in hearts of mice is directly linked to proper cardiac muscle contraction, rhythm and maintenance of 2) ___ activity. The near total absence of calcineurin in mice leads to heart arrhythmia, failure and 3) ___. It was previously known that 4) ___ is important to heart function, but the extent of its role had not been defined prior to the current study. Although the research involved mice, it offers important insights for future studies that could lead to new approaches in diagnosis and treatment of heart patients, said Marjorie Maillet, Ph.D., the study's first author. "We found that when you eliminate calcineurin, a pool of genes that regulates 5) ___ in the heart went awry. This leads to defects in the growth and proliferation of heart cells, heart disease, arrhythmia, loss of contractility and heart failure and disease," said Dr. Maillet. Calcium is also important to cardiac growth and the contraction of heart 6) ___. Previous studies have linked abnormalities in calcium handling to cardiac disease, especially in adults. In mice genetically bred for calcineurin deficiency, the researchers saw that this deficiency causes a dramatic reduction in the expression of 7) ___ that coordinately regulate calcium-handling and contraction. The scientists also report a newly identified "feed-forward" mechanism, in which the direct activation of calcineurin by calcium augments the expression of genes that regulate calcium-handling 8) ___ in the heart.

ANSWERS: 1) enzyme; 2) heart; 3) death; 4) calcineurin; 5) calcium; 6) muscle; 7) genes; 8) proteins 

King Tutankhamun (King Tut 1341-1323 BCE)

Two years of DNA testing and CT scans on King Tutankhamun's 3,300-year-old mummy and 15 other mummies are helping end many of the myths surrounding the boy king. While a comparatively minor ruler, he has captivated the public since the 1922 discovery of his tomb, which was filled with a stunning array of jewels and artifacts, including a golden funeral mask. The study, which was published this past Wednesday in the Journal of the American Medical Association, provides the firmest family tree yet for Tut. The tests pointed to Pharaoh Akhenaten, who tried to revolutionize ancient Egyptian religion to worship one god, as Tut's father. His mother was one of Akhenaten's sisters. King Tutankhamun, was a frail boy who suffered from a cleft palate and club foot. He died of complications from a broken leg exacerbated by malaria and his parents were most likely brother and sister. Tut, who became pharaoh at age 10 in 1333 BCE, ruled for just nine years at a pivotal time in Egypt's history. Speculation has long swirled over his death at 19. A hole in his skull fueled speculation he was murdered, until a 2005 CT scan ruled that out, finding the hole was likely from the mummification process. The scan also uncovered the broken leg. The newest tests paint a picture of a pharaoh whose immune system was likely weakened by congenital diseases. His death came from complications from the broken leg, along with a new discovery: severe malaria. The team said it found DNA of the malaria parasite in several of the mummies. A sudden leg fracture possibly introduced by a fall might have resulted in a life threatening condition when a malaria infection occurred. Tutankhamun might be envisioned as a young but frail king who needed canes to walk. The revelations are in stark contrast to the popular image of a graceful boy-king as portrayed by the dazzling funerary artifacts in his tomb that later introduced much of the world to the glory of ancient Egypt. They also highlighted the role genetics play in some diseases. The members of the 18th dynasty were closely inbred and the DNA studies found several genetic disorders in the mummies tested such as scoliosis, curvature of the spine, and club feet. Dr. Howard Markel, a medical historian at the University of Michigan, said some of King Tut's ailments including his bone disease likely were the result of his parents' incestuous marriage. Like his father, Tutankhamun had a cleft palate. Like his grandfather, he had a club foot and suffered from Kohler's disease which inhibits the supply of blood to the bones of the foot. In Tut's case it was slowly destroying the bones in his left foot, an often painful condition. The study noted that 130 walking sticks and canes were discovered in Tut's tomb, some of them appeared to have been used. Egypt's top archaeologist, Zahi Hawass, who co-authored the study, noted that more than 80 years after Tutankhamun's discovery, technology was revealing secrets about the pharaoh. The study is part of a wider program to test the DNA of hundreds of mummies to determine their identities and their family relations. To conduct the tests, Egypt built two DNA labs to follow international protocols for genetic testing. The new study answered long-standing questions about Tutankhamun's family, tracing his grandfather to Pharaoh Amenhotep III. While some archaeologists have speculated that Tut's father was a little-known figure, Smenkhkare, it now appears that it was Akhenaten, who attempted to change millennia of religious tradition by forcing the country to worship the sun god Aten, instead of a multiplicity of deities. DNA tests pinpointed the mummy of Tut's mother and confirmed she was a sister of his father. Brother-sister marriages were common among Egypt's pharaohs. The tests also disproved speculation that Tutankhamun and members of his family suffered from rare disorders that gave them feminine attributes and misshapen bones, including Marfan syndrome, a connective tissue disorder that can result in elongated limbs. The theories arose from the artistic style and statues of the period, which showed the royal men with prominent breasts, elongated heads and flared hips. The first high profile discovery involving DNA tests, the identification of the mummy of Queen Hatshepsut, came under criticism because it didn't follow accepted scientific protocols and was not published in a peer-reviewed scientific journal. The tests were also not confirmed by a second, independent DNA lab. This time the work by the Supreme Council of Antiquities DNA lab was replicated by a second DNA lab set up at Cairo University. Angelique Corthals, an assistant professor of forensic science at the John Jay College of Criminal Justice in New York helped set up the first Egyptian lab and said the work is being conducted according to international standards.

Preoperative Briefing in the Operating Room

Contemporary preoperative team briefings conducted to improve patient safety focus mainly on supplying identification details regarding the patient and the surgical procedure. According to an article published in Chest (2010;137:443-449), drawing on cognitive theory principles, a briefing protocol was developed that presents a broader perspective model of the patient and the planned procedure. In addition to customary identification details and drug sensitivities, the new briefing also includes review of significant background information, needed equipment, planned surgery stages, and so forth. The briefing content was developed following 130 continuous, non-structured observations conducted in gynecologic and orthopedic operating rooms. The briefing form was designed as a large poster hung in a visible position on the operating room wall. The poster guides the team members (i.e., nurses, surgeons, and anesthesiologists) in their conduct. Briefing is conducted orally, and no written records are required. The number of non-routine events (i.e., situations that, if not corrected, might lead to patient harm) observed in the 130 surgeries conducted without briefing was compared with the number of events in 102 surgeries in which briefing was conducted. Results showed that there was a 25% reduction in the number of non-routine events when briefing was conducted and a significant increase in the number of surgeries in which no non-routine event was observed. Team members evaluated the briefing as most valuable for their own work, the teamwork, and patient safety. Following the study, the new briefing format was accepted and adopted for routine use. Team briefings designed to supply a broader-perspective surgery model may be an easy-to-apply tool to reduce the number of non-routine events during surgery and increase patient safety.

Dynamics of Obesity and Chronic Health Conditions Among Children and Youth

Rates of obesity and other childhood chronic conditions have increased over recent decades. Patterns of how conditions change over time have not been widely examined. As a result, a study published in the Journal of the American Medical Association (2010;303:623-630), was performed to evaluate the change in prevalence of obesity and other chronic conditions in US children, including incidence, remission, and prevalence. The investigation was a prospective study using the National Longitudinal Survey of Youth-Child Cohort (1988-2006) of 3 nationally representative cohorts of children. Children were aged 2 through 8 years at the beginning of each study period, and cohorts were followed up for 6 years, from 1988 to 1994 (cohort 1, n = 2337), 1994 to 2000 (cohort 2, n = 1759), and 2000 to 2006 (n = 905). The main outcome measures were parent report of a child having a health condition that 1) limited activities or schooling or 2) required medicine, special equipment, or specialized health services and 30 that lasted at least 12 months. Obesity was defined as a body mass index at or above the 95th percentile for age. Chronic conditions were grouped into 4 categories: obesity, asthma, other physical conditions, and behavior/learning problems. Results showed that the end-study prevalence of any chronic health condition was 12.8% for cohort 1 in 1994, 25.1% for cohort 2 in 2000, and 26.6% for cohort 3 in 2006. There was substantial turnover in chronic conditions: 7.4% of participants in all cohorts had a chronic condition at the beginning of the study that persisted to the end, 9.3% reported conditions at the beginning that resolved within 6 years, and 13.4% had new conditions that arose during the 6-year study period. The prevalence of having a chronic condition during any part of the 6-year study period was highest for cohort 3 (51.5%), and there were higher rates among male (adjusted odds ratio [AOR], 1.24), Hispanic (AOR, 1.36), and black (AOR, 1.60) youth.

Effect of Dietary Salt Reductions on Future Cardiovascular Disease Can Save Billions Per Year and Pay For Health Insurance Reform

The U.S. diet is high in salt, with the majority coming from processed foods. Reducing dietary salt is a potentially important target for the improvement of public health. As a result, a study published in the New England Journal of Medicine (2010; 362:590-599) used the Coronary Heart Disease (CHD) Policy Model to quantify the benefits of potentially achievable, population-wide reductions in dietary salt of up to 3 g per day (1200 mg of sodium per day). The study estimated the rates and costs of cardiovascular disease in subgroups defined by age, gender, and race; compared the effects of salt reduction with those of other interventions intended to reduce the risk of cardiovascular disease; and determined the cost-effectiveness of salt reduction as compared with the treatment of hypertension with medications. Results showed that reducing dietary salt by 3 g per day is projected to reduce the annual number of new cases of CHD by 60,000 to 120,000, stroke by 32,000 to 66,000, and myocardial infarction by 54,000 to 99,000 and to reduce the annual number of deaths from any cause by 44,000 to 92,000. All segments of the population would benefit, with African Americans benefiting proportionately more, women benefiting particularly from stroke reduction, older adults from reductions in CHD events, and younger adults from lower mortality rates. The cardiovascular benefits of reduced salt intake are on a par with the benefits of population-wide reductions in tobacco use, obesity, and cholesterol levels. A regulatory intervention designed to achieve a reduction in salt intake of 3 g per day would save 194,000 to 392,000 quality-adjusted life-years and $10 billion to $24 billion in health care costs annually. Such an intervention would be cost-saving even if only a modest reduction of 1 g per day were achieved gradually between 2010 and 2019 and would be more cost-effective than using medications to lower blood pressure in all persons with hypertension. According to the authors, modest reductions in dietary salt could substantially reduce cardiovascular events and medical costs and should be a public health target.

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.

Critical Path Initiative

The "Critical Path" is the scientific process through which a potential human drug, biological product, or medical device is transformed from a discovery or “proof of concept“ into a medical product. It consists of scientific tests and tools used to predict whether a product candidate will be safe and effective, to assess how prototypes interact with the human body, and to guide the sponsor in choosing an appropriate dose and regimen or device size and/or placement. It consists of scientific tools to manufacture the product at commercial scale and assess the quality of the manufactured product. In order to bring a product to market successfully and efficiently, product sponsors need scientifically sound approaches to these challenges.

What is a Critical Path tool?

Critical path tools are scientific or technical methods used to:

1.       Predict whether a product candidate will be safe and effective, so the sponsor can decide which candidates to move to each successively more rigorous phase of testing,

2.       Assess whether a product candidate is safe and effective, once the potential product is moved into human testing, or

3.       Manufacture large amounts of the product, and assess the quality of the finished product.

4.       Examples include:

a)       Animal models of human disease - used to predict whether potential products will ameliorate the target condition and/or be toxic to humans.

b)       “Biomarkers“ - physiologic indicators (e.g., blood protein levels) that can be used to measure the progress of a disease or the effects of a treatment, often long before other indications are apparent in a patient.

c)       Clinical trial designs - the scientific protocols that reliably assess the effects of a potential product on humans.

d)       Quality assessment technologies - used to analyze product quality (e.g., durability of devices, stability of drugs).

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*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.