Economic Impact of Direct Data Entry (DDE)



Pharmaceutical companies, CROs, and clinical sites spend millions to manage the vast amount of paperwork that regulatory agencies require during the drug and device development process. Currently, each clinical research site must maintain original source documents/data for the required document retention period. Our friends at Clinical Leader wrote an article on The Economic Impact of Using Target e*CTR® (Target e*Clinical Trial Record; patent pending). The Target e*CTR process allows a clinical study site to perform direct data entry of original source data into Target e*CRF® (or any EDC system), and to store these original data in human readable format in the Target e*CTR Viewer (or an equivalent viewer). The Viewer acts as an independent repository of original data, access to which is controlled by the clinical investigator prior to the data being recorded in the EDC database.


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

Inflammation Is Controlled Differently in Brain and Other Tissues




A team led by scientists from The Scripps Research Institute has identified a new metabolic pathway for controlling brain inflammation, suggesting strategies for treating it. The new report, which appeared in the October 20, 2011 edition of Science Express, focuses on the type of inflammation normally treatable with non-steroidal anti-inflammatory drugs (NSAIDs), such as 1) ___ or ibuprofen. The study shows this type of inflammation is controlled by different enzymes in different parts of the body.


“Our findings open up the possibility of anti-inflammatory drugs that are more tissue-specific and don’t have NSAIDs’ side effects,” said the study’s senior author Benjamin F. Cravatt, chair of the Department of Chemical Physiology and member of the Skaggs Institute for Chemical Biology and the Dorris Neuroscience Center at Scripps Research.


A Serendipitous Discovery


The serendipitous discovery originated with an attempt by Cravatt and his colleagues to develop a new kind of pain-relieving drug targeting an enzyme known as monoacylglycerol lipase (MAGL). This enzyme normally breaks down a natural 2) ___-relieving neurotransmitter known as 2-AG, a “cannabinoid” molecule whose actions are mimicked by certain compounds within marijuana. To reduce the rate of 2-AG breakdown, allowing 2-AG levels to rise and provide more pain relief, the Cravatt lab developed a powerful and selective MAGL-inhibiting compound, which the scientists described in 2009 and are still investigating as a possible pain 3) ___.


In the course of this research, the scientists tested their MAGL inhibitor on mice and also engineered mice that genetically lack MAGL. “We noticed that the brains of the MAGL-inhibited mice showed reduced levels of arachidonic acid, a key precursor molecule for inflammatory lipids,” said Daniel Nomura, a former member of the Cravatt lab who is currently assistant professor in the Department of Nutritional Science & Toxicology at the University of California, Berkeley.


Arachidonic acid had been thought to originate similarly throughout the 4) ___, from a process involving fat molecules and phospholipase A2 enzymes. To their surprise, the researchers found that in the brain, arachidonic acid production is controlled chiefly by MAGL. In effect, the enzyme takes pleasure-associated 2-AG, which is found in high concentrations in the 5) ___, and turns it into arachidonic acid — the precursor for pain- and inflammation-causing prostaglandin molecules. The researchers showed that blocking the activity of MAGL, or genetically eliminating it, shrinks the pool of arachidonic acid and prostaglandins in mouse brains, effectively limiting the possibility of brain inflammation.


Providing a Protective Effect


To further test this effect, the researchers set up two standard models of brain inflammation in lab mice. In one, they tried to induce inflammation with lipopolysaccharide, a highly pro-inflammatory molecule found in bacteria. In the other, they used the toxin MPTP, which induces brain 6) ___ and preferentially kills the same muscle-regulating neurons lost in Parkinson’s disease.


“In both models, reducing MAGL — genetically or with our MAGL-inhibitor -provided the animals with protection from neuroinflammation,” said Nomura, who is continuing to research the system at UC Berkeley.


NSAIDs such as 7) ___ are already used to reduce the inflammation that originates from arachidonic acid. They work by inhibiting the cyclo-oxygenase enzymes that convert arachidonic acid into prostaglandins. But NSAIDs also inhibit cyclo-oxygenase enzymes that protect the lining of the gastrointestinal tract. They thus can cause gastrointestinal bleeding, among other adverse side effects. That greatly limits their potential usefulness. In the brain, where MAGL is the major controller of arachidonic acid levels, blocking the enzyme could be a better strategy. Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, and traumatic brain injury all involve harmful but potentially treatable brain inflammation.


“In principle, with a MAGL inhibitor we could avoid the gastrointestinal toxicity that’s associated with NSAIDs while still maintaining the anti-inflammatory effect,” said Nomura.


Unexpected Elements

The new findings also are important from a basic science perspective because they advance the understanding of prostaglandin-mediated inflammation. Phospholipase A2 enzymes have long been considered the dominant producers of arachidonic acid, and thus a major element in 8) ___ -mediated inflammation throughout the body. Nomura, Cravatt, and their colleagues confirmed in their experiments that phospholipase A2 enzymes play a major role in arachidonic acid production in the gut and spleen. However, in the brain, the MAGL enzyme was the principal regulator, with phospholipase A2 enzymes making a more limited contribution. MAGL also regulated arachidonic acid and prostaglandins in liver and lungs.


“Biological pathways that we think we understand sometimes turn out to have these unexpected, tissue- or context-specific elements, which is why it’s so important to follow up on clues such as the ones we found,” Cravatt said. The research was supported by the National Institutes of Health, the Institute for Drug and Alcohol Studies at Virginia Commonwealth University, the Ellison Medical Foundation, and the Skaggs Institute for Chemical Biology at Scripps Research Institute.




1) aspirin; 2) pain; 3) drug; 4) body; 5) brain; 6) inflammation; 7) ibuprofen; 8) prostaglandin


Ernst von Fleischl-Marxow MD (1846-1891)


Ernst von Fleischl-Marxow



Ernst von Fleischl-Marxow (1846 – 1891) was an Austrian physiologist and physician who became known for his important investigations on the electrical activity of nerves and the brain. He was also a creative inventor of new devices which were widely adopted in clinical medicine and physiological research. Marxow studied medicine in the University of Vienna, Austria. He started his scientific career as a research assistant in the laboratory of Ernst Wilhelm von Brücke (1819–1892), and later as an assistant, in the same University, to the eminent pathologist Carl von Rokitansky (1804–1878). Unfortunately, an accident while he was dissecting a cadaver injured his thumb, which became infected and had to be amputated, interrupting his activities in anatomical pathology. Thus, he had to turn to Physiology, and he came back to von Brucke’s laboratory in Vienna after studying for a year with Carl Ludwig (1816–1895), another famous physiologist at the University of Leipzig, Germany


In the first phase of his career in neurophysiology, Marxow dedicated himself to electrophysiology of nerves and muscles, after the pioneering investigations of Emil du Bois-Reymond (1818–1896), who had discovered the action potentials of axons. This field highly benefitted from the technical developments occurring in the physical sciences, particularly new devices which were invented to work with small electric potentials and currents. Since biological tissues have extremely low levels of electrical activity (in the range of microvolts), neurophysiology’s progress had to wait for them. Like many German physiologists of his time, Marxow had a good knowledge and ability with physics, and invented a number of devices for the purpose of his studies, particularly the reonome (a kind of rheostat, or variable resistor used to control finely the intensity of an electrical stimulus). He also adapted the Lippmann’s capillary electrometer in order to use it for measuring subtle bioelectrical phenomena.


From the bioelectricity of nerves, Marxow turned his attention, from 1876 on, to the global electrical activity of the cerebral hemispheres. Neuroanatomists had already determined at the time that its nervous tissue was also composed of cells (the neurons), with their bodies mainly located in the gray matter, and filamentary prolongations, the dendrites and the axons. Thus, it was only natural to assume that they would also display electrical activity. This important discovery, however, had not been made until that time, because many desynchronized electrical potentials with different polarities produce a cumulative global potential which is actually very small and difficult to detect with the sensitivity range of the measuring devices available at the time. Despite this, Marxow was able to prove for the first time that the peripheral stimulation of sensory organs, such as vision and hearing were able to provoke event-related small electrical potential swings on the surface of the cerebral cortex which was related to the projection of those senses. Strangely, however, Marxow did not publish his results, choosing instead to deposit them in a bank safe, with instructions to reveal them in 1883 only. Meanwhile, the first publications about what was later to be called the electroencephalogram came to light, independently demonstrated by Richard Caton (1842–1926), in Great Britain, and Adolf Beck (1863–1942) in Poland, both using laboratory animals.


With his increasing knowledge in optical physics, Marxow developed several optical measurement instruments, such as an spectropolarimeter and a hematometer (a device used for measuring the content of hemoglobin in the blood), which was named in his honor, and which for many years found wide application in laboratory medicine and diagnostic hematology.


For many years, Marxow labored under intense personal suffering, due to chronic painful complications of his amputation. Because of this, he became an addict of morphine and heroin. Sigmund Freud, then a Viennese neurologist, was one of his most intimate friends. At the time, Freud was studying the medical properties of cocaine, and was convinced that cocaine could be not only be used as mild euphoriant, aphrodisiac and analgesic, but also as a treatment for morphine addicts. He recommended this to his friend Marxow, who then got a much worse addiction to cocaine. Devastated by pain and disease, Marxow died on October 22, 1891, at only 45 years of age.


Malaria Vaccine from GSK with Support from the Gates Foundation is Efficacious



While a malaria vaccine is a major breakthrough and clearly needed, until there is adequate mosquito control, it will be impossible to control the multitudes of mosquito-borne diseases. Arthropod (arbo)-borne diseases, i.e., are diseases that are maintained in nature through biological transmission between susceptible vertebrate hosts by blood feeding arthropods (mosquitoes, ticks, etc.). Vertebrate infection occurs when the infected arthropod takes a blood meal.


Each year, malaria occurs in approximately 225 million persons worldwide, and 781,000 persons, mostly African children, die from the disease. During the past decade, the scale-up of malaria-control interventions has resulted in considerable reductions in morbidity and mortality associated with malaria in parts of Africa. However, malaria continues to pose a major public health threat. A malaria vaccine, deployed in combination with current malaria-control tools, could play an important role in future control and eventual elimination of malaria in Africa.


According to articles published online in the New England Journal of Medicine (18 October 2011) and in The Lancet Infectious Diseases (2011;11:741-749), results are now available from studies of the efficacy, safety, and immunogenicity of candidate malaria vaccine RTS,S/AS01 being conducted in seven African countries. The following is from the article in the NEJM.


From March 2009 through January 2011, the study enrolled 15,460 children in two age categories – 6 to 12 weeks of age and 5 to 17 months of age – for vaccination with either RTS,S/AS01 or a non-malaria comparator vaccine. The primary end point of the analysis was vaccine efficacy against clinical malaria during the 12 months after vaccination in the first 6,000 children 5 to 17 months of age at enrollment who received all three doses of vaccine according to protocol. After 250 children had an episode of severe malaria, the study evaluated vaccine efficacy against severe malaria in both age categories.


Results showed that In the 14 months after the first dose of vaccine, the incidence of first episodes of clinical malaria in the first 6,000 children in the older age category was 0.32 episodes per person-year in the RTS,S/AS01 group and 0.55 episodes per person-year in the control group. This translates into an efficacy of 50.4% in the intention-to-treat (ITT) population and 55.8%. Vaccine efficacy against severe malaria was 45.1% in the ITT population. Vaccine efficacy against severe malaria in the combined age categories was 34.8% (95% CI, 16.2 to 49.2) in the per-protocol population during an average follow-up of 11 months. Serious adverse events occurred with a similar frequency in the two study groups.


According to the authors, the RTS,S/AS01 vaccine provided protection against both clinical and severe malaria in African children. The program is funded by GlaxoSmithKline Biologicals and the PATH Malaria Vaccine Initiative (MVI). MVI is a global program of the international nonprofit organization PATH and was established in 1999 through a grant from the Bill & Melinda Gates Foundation.

Commonly Used 3-Drug Regimen for Idiopathic Pulmonary Fibrosis Found Harmful


A lung-scarring disease, idiopathic pulmonary fibrosis (IPF) is a progressive and currently incurable disease characterized by the buildup of fibrous scar tissue within the lungs. This accumulation of scar tissue leads to breathing difficulties, coughing, chest pain, and fatigue. Approximately 200,000 people in the US have IPF. The cause or causes of IPF remain unknown.


The National Heart, Lung, and Blood Institute (NHLBI), part of the National Institutes of Health, has stopped one arm of a three arm multi-center, clinical trial studying treatments for the IPF for safety concerns. The trial found that people with IPF receiving a currently used triple-drug therapy consisting of prednisone, azathioprine, and N-acetylcysteine (NAC) had worse outcomes than those who received placebos or inactive substances. The study had enrolled 238 of a planned 390 participants prior to the stop announcement. Participants ranged from 48 to 85 years of age, with an average age of 68.


The study, called PANTHER-IPF (Prednisone, Azathioprine, and N-acetylcysteine: A Study that Evaluates Response in Idiopathic Pulmonary Fibrosis) was designed and conducted by the Idiopathic Pulmonary Fibrosis Clinical Research Network, funded by the NHLBI. The PANTHER-IPF study was designed to evaluate whether this commonly used triple-therapy regimen could slow disease progression and improve lung function in people with moderate IPF. PANTHER-IPF was the first study in IPF comparing the effectiveness of this combined treatment to a placebo for all three drugs. Each participant had a one in three chance of being randomized to receive the triple drug regimen, NAC alone, or placebo for a period of up to 60 weeks.


The interim results from this study showed that compared to placebo, those assigned to triple therapy had greater mortality (11% versus 1%), more hospitalizations (29% versus 8%), and more serious adverse events (31% versus 9%) and also had no difference in lung function test changes. Participants randomly assigned to the triple- therapy arm also remained on their assigned treatment at a much lower rate (78% adherence versus 98% adherence).


The other two study arms, or intervention groups, of this IPF trial comparing NAC alone to placebo alone will continue. In stopping this part of the trial, the NHLBI accepted the recommendation of the Data and Safety Monitoring Board (DSMB) – an independent advisory group of experts in lung disease, biostatistics, medical ethics, and clinical trial design. The DSMB has been monitoring the study since it began.


According to the authors, anyone on some combination of these medications with questions or concerns should consult with their health care provider and not simply stop taking the drugs, but that it is also important to realize that these results definitively apply only to patients with well-defined IPF and not to people taking a combination of these drugs for other lung diseases or conditions.

Conditions of Long-term Success in a Lifestyle Intervention for Overweight and Obese Youths



Childhood lifestyle interventions usually involve the families. However, knowledge of family characteristics that promote or constrain a child’s weight-reduction outcome is limited. Candidates for such factors might be family characteristics that have proven to be associated with social adjustment (development) in childhood. As a result, a study published in Pediatrics (2011;128:779-785), was designed to analyze whether family adversity, maternal depression, and attachment insecurity predict long-term success in children’s weight reduction.


Study participants included 111 parent-child dyads with overweight and obese children/adolescents aged between 7 and 15 years with a mean BMI of 29.07 (range: 21.4-44.9). The families took part in a best-practice lifestyle intervention of 1 year’s duration. A longitudinal analysis with 3 assessment waves (baseline, conclusion, 1-year follow-up) was conducted.


Results revealed that long-term success (at least 5% weight reduction by the 1-year follow-up) versus failure (dropping out or less weight reduction) was significantly predicted by the set of psychosocial variables (family adversity, maternal depression, and attachment insecurity), the controlled for familial obesity, pre-intervention overweight, age, and gender of the index child and parental educational level. Maternal depression proved to be the best predictor. Maintenance of weight reduction between the conclusion of the program and the 1-year-follow-up was also predicted by the set of psychosocial variables. Maternal insecure-anxious attachment attitudes best predicted this criterion.


According to the authors, although cross-validation is required, the results are the first evidence for proximal and distal family characteristics linked to long-term weight-reduction outcomes. The authors added that the results suggest a need to create tailored intervention modules that address the difficulties of these families.

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


Defining Essential Benefits – A Role for Cost?


By Mark L. Horn MD, MPH, CMO Target Health Inc.


Efforts to isolate cost concerns from benefit decisions under the implementation of the Affordable Care Act received a significant challenge earlier this month when the Institute of Medicine (IOM) released its report on the process for designing an Essential Health Benefits (EHB) Package on October 7th. Consistent with precedent established in virtually all discussions of health policy, the report recommends transparency and stakeholder input in developing, monitoring and modifying (over time) the elements of the Package. However, potentially challenging to many constituencies, IOM also recognizes and emphasizes that the plan must be financially responsible. Over time its growth rate should correlate with the overall growth of the economy.


The IOM Report was requested by the Department of Health and Human Services as a consequence of its own charge under the Affordable Care Act to develop a package of essential benefits equivalent to those offered in typical employer plans. The Department charged the IOM with crafting a process for defining these essential benefits, but did not ask that IOM delineate the actual benefits. This latter task, actually defining benefits, demands a more inclusive and public process.


The process promulgated by the IOM will require choices, and there is explicit recognition that cost should (must?) play a role in these choices. Therefore, along with the requisite requirements for transparency and public input, there is explicit recognition that managing costs is important to both keep premiums affordable and, since the plans will be subsidized for many individuals and families, keep federal expenditures rational.


This will not be an easy task since the Affordable Care Act requires the inclusion of 10 broad benefit categories, including several that potentially expand coverage beyond that characteristically offered, and therefore have costs that are difficult to predict.


In sum then, the IOM Report has placed cost issues squarely in the “bulls-eye” for public debate. If the Affordable Care Act is to succeed in covering the uninsured with a fiscally sustainable benefits package not only must the issue of reducing health care costs be engaged, it must be engaged by both public and private stakeholders, including providers, patients, payers, and the organizations that represent them.


It is often said that a problem cannot be solved until it is properly defined. The IOM has not solved the problem of rising health costs; that was not their remit. However, by defining the problem and calling out all stakeholders, including patients and public and private sector health system advocates, to come together in order to solve it, the IOM has placed the responsibility for making the tough calls on all of us, precisely where it belongs.