Patent Office Issues Notice of Allowance For eSource Software





Target Health has received a Notice of Allowance from the US Patent Office for Target e*CTR® (Target e*Clinical Trial Record). Target e*CTR is the electronic clinical trial patient record, access to which is controlled by the clinical investigator. Target e*CTR is created at the time data are initially entered into any electronic data base, but before the data are entered into the sponsor’s or EDC database. Therefore, Target e*CTR can be considered the original patient record (source document) associated with the patient record when direct data entry (DDE) occurs at the patient visit. Target e*CTR can be integrated seamlessly with any EDC and EHR system and does NOT affect any end-user or workflow of any EDC system, thus does not require any training. A ROI analysis indicates a minimum savings of $6,000 per clinical site if monitoring visits drop from 5 to 3 in a 1-year study, and $10,000/site if visits drop from 6 to 3.


Target Health just finished its first study using Target e*CTR and is starting its next study this month. An NDA planned Q4 2012. The following are the results of the first study:


  1. Screening errors picked up early
  2. Real time monitoring at the time of data entry
  3. No need to do additional subject recruitment
  4. EDC edit checks modified early in the game
  5. Compliance issues identified in real time
  6. Immediate availability of safety issues
  7. Site saved 70 hours of data entry time
  8. Nothing to do after patient left the clinic


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

Protein Switches Could Turn Cancer Cells Into Tiny Chemotherapy Factories


Brain Cancer Cell



Breast Cancer Cell



Johns Hopkins researchers have devised a protein “switch” that instructs cancer cells to produce their own anti-cancer medication. In lab tests, the researchers showed that these switches, working from inside the cells, can activate a powerful cell-killing drug when the device detects a marker linked to cancer. The goal, the scientists said, is to deploy a new type of weapon that causes cancer cells to self-destruct while sparing healthy 1) ___.


This new cancer-fighting strategy and promising early lab test results were reported this week in the online early edition of Proceedings of the National Academy of Sciences (DOI: 10.1073/pnas.1102803108). Although the switches have not yet been tested on 2) ___ patients, and much more testing must be done, the researchers say they have taken a positive first step toward adding a novel weapon to the difficult task of treating cancer.


One key problem in fighting cancer is that broadly applied chemotherapy usually also harms healthy 3) ___. In the protein switch strategy, however, a doctor would instead administer a “prodrug,” meaning an inactive form of a cancer-fighting drug. Only when a cancer marker is present would the cellular switch turn this harmless prodrug into a potent form of chemotherapy. “The switch in effect turns the cancer cell into a factory for producing the anti-cancer 4) ___ inside the cancer cell,” said Marc Ostermeier, a Johns Hopkins chemical and biomolecular engineering professor in the Whiting School of Engineering, who supervised development of the switch. “The healthy cells will also receive the 5) ___,” he added, “and ideally it will remain in its non-toxic form. Our hope is that this strategy will kill more cancer cells while decreasing the unfortunate side effects on healthy cells.”


To demonstrate that these switches can work, the research team successfully tested them on human colon cancer and breast 6) ___ cells in Ostermeier’s lab and in the laboratory of James R. Eshleman, a professor of pathology and oncology in the Johns Hopkins School of Medicine. “This is a radically different tool to attack cancers,” said Eshleman, a co-author of the PNAS journal article, “but many experiments need to be done before we will be able to use it in patients.” The next step is animal testing, expected to begin within a year, Ostermeier said.


Ostermeier’s team made the cancer-fighting switch by fusing together two different proteins. One protein detects a marker that cancer cells produce. The other 7) ___, from yeast, can turn an inactive prodrug into a cancer-cell killer. “When the first part of the switch detects cancer, it tells its partner to activate the chemotherapy drug, destroying the cell,” Ostermeier said. In order for this switch to work, it must first get inside the cancer cells. Ostermeier said this can be done through a technique in which the switch gene is delivered inside the cell. The switch 8) ___ serves as the blueprint from which the cell’s own machinery constructs the protein switch. Another approach, he said, would be to develop methods to deliver the switch protein itself to cells. Once the switches are in place, the patient would receive the inactive chemotherapy drug, which would turn into a cancer attacker inside the cells where the switch has been flipped 9) ___.


Although many researchers are developing methods to deliver anti-cancer drugs specifically to cancer cells, Ostermeier said the protein switch tactic skirts difficulties encountered in those methods. “The protein 10) ___ concept changes the game by providing a mechanism to target production of the anti-cancer drugs inside cancer cells instead of targeting delivery of the anti-cancer drug to cancer cells,” he said.


ANSWERS: 1) tissue; 2) human; 3) cells; 4) drug; 5) prodrug; 6) cancer; 7) protein; 8) gene; 9) on; 10) switch


Urine and Medicine


A Doctor Examining Urine — Date painted: First half of 17th Century



Many physicians in history have resorted to the inspection and examination of the urine of their patients. Hermogenes, a Greek physician who probably lived in the third or second century BCE, wrote about the color and other attributes of urine as indicators of certain diseases. Abdul Malik Ibn Habib of Andalusia (southern Iberia or Spain) d.862 CE, mentions numerous reports of urine examination throughout the Umayyad empire. Diabetes mellitus got its name because the urine is plentiful and sweet.


A urinalysis is a medical examination of the urine and part of routine examinations. A culture of the urine is performed when a urinary tract infection is suspected. A microscopic examination of the urine may be helpful to identify organic or inorganic substrates and help in the diagnosis. The color and volume of urine can be reliable indicators of hydration level. Clear and copious urine is generally a sign of adequate hydration, dark urine is a sign of dehydration. The exception occurs when alcohol, caffeine, or other diuretics are consumed, in which case urine can be clear and copious and the person still be dehydrated.


In Roman times, there was a tradition among the Gauls to use urine to brush and whiten teeth. This practice lasted into the Renaissance. Ancient Romans used human urine to cleanse grease stains from their clothing, before acquiring soaps from the Germans during the first century CE. Urine that has been fermented for the purposes of cleaning is referred to as lant. The emperor Nero instituted a tax (Latin: vectigal urinae) on the urine industry. This tax was continued by Nero’s successor, Vespasian, to whom is attributed the Latin saying Pecunia non olet (money doesn’t smell) – this is said to have been Vespasian’s reply to a complaint from his son about the disgusting nature of the tax. Vespasian’s name is still attached to public urinals in France (vespasiennes), Italy (vespasiani), and Romania (vespasiene).


From the first millennium BCE to about 500 CE, foundational works of religious Sanskrit text contain stanzas on the benefits of “pure water, or one’s own urine”. In this text, urine therapy is referred to as Shivambu Kalpa. This ancient Indian text suggests, among other uses and prescriptions, massaging one’s skin with fresh, concentrated urine. Alchemists spent much time trying to extract gold from urine, and this effort led to discoveries such as white phosphorus, which was discovered by the German alchemist Hennig Brand in 1669 when he was distilling fermented urine. In 1773 the French chemist Hilaire Rouelle discovered the organic compound urea by boiling urine dry.


The word “urine” was first used in the 14th century. Before that, the concept was described by the now vulgar word “piss”. Onomatopoetic in origins, “piss” was the primary means of describing urination, as “urinate” was at first used mostly in medical contexts. Likely, “piss” became vulgar through its use by lower class characters such as the Reeve and the Wife of Bath in Geoffrey Chaucer’s 14th century work The Canterbury Tales.


The last great Byzantine physician was John Actuarius, who lived in the early 14th Century in Constantinople. His works on urine laid much of the foundation for later study in that field. However, from the latter 12th Century to the end in 1453, there is very little outpouring in medical knowledge, largely due to the turmoil the Empire was facing on both fronts, following its resurrection after the Roman Empire and the dwindling population of Constantinople due to plague and war.


One standard authority for drugs in Europe until the end of the eighteenth century was Lamery’s Dictionnaire Universelle des Drogues. One of the late editions, published in 1759, contains a list of remedies under “Homo.” It explains: “All parts of man, his excrescences and excrements, contain oil and the sals volatile, combined with phlegm and earth…” The book recommends the drinking of two or three glasses of urine each morning to cure gout, to relieve obstructions of the bowels, and to dispel hysterical vapors.


In the early 1800s, a book titled One Thousand Notable Things describes the use of urine to cure scurvy, relieve skin itching, cleanse wounds, and many other treatments. An 18th century French dentist praised urine as a valuable mouthwash. In England during the 1860-70s, the drinking of one’s own urine was a common cure for jaundice. In more modern times, the Alaskan Eskimos have used urine as an antiseptic to treat wounds.


In China, the urine of young boys was regarded as a curative. In southern China, babies’ faces were washed with urine to protect the skin. In France, a cure for strep throat was to soak stockings in urine and wrap them around their necks. Aristocratic French women in the 17th century reportedly bathed in urine to beautify their skin. In Sierra Madre, Mexico, farmers prepared poultices for broken bones by having a child urinate into a bowl of powdered charred corn. The mixture was made into a paste and applied to the skin.

Intranasal Insulin Therapy for Alzheimer Disease and Amnestic Mild Cognitive Impairment



According to an article published online in the Archives of Neurology 12 September 2011, a randomized, double-blind, placebo-controlled clinical trial was performed at a clinical research unit of a Veterans Affairs medical center in order to examine the effects of intranasal insulin administration on cognition, function, cerebral glucose metabolism, and cerebrospinal fluid biomarkers in adults with amnestic mild cognitive impairment or Alzheimer disease (AD).


The study sample consisted of 104 adults with amnestic mild cognitive impairment (n = 64) or mild to moderate AD (n = 40) who received placebo (n = 30), 20 IU of insulin (n = 36), or 40 IU of insulin (n = 38) for 4 months, administered with a nasal drug delivery device (Kurve Technology, Bothell, Washington). The primary outcome measure was delayed story recall score and the Dementia Severity Rating Scale score, and the secondary measures included the Alzheimer Disease’s Assessment Scale–cognitive subscale (ADAS-cog) score and the Alzheimer’s Disease Cooperative Study–activities of daily living (ADCS-ADL) scale. A subset of participants underwent lumbar puncture (n = 23) and positron emission tomography with fludeoxyglucose F 18 (n = 40) before and after treatment.


Results showed that treatment with 20 IU of insulin improved delayed memory (P <0.05), and both doses of insulin (20 and 40 IU) preserved caregiver-rated functional ability (P <0.01). Both insulin doses also preserved general cognition as assessed by the ADAS-cog score for younger participants and functional abilities as assessed by the ADCS-ADL scale for adults with AD (P <.005).


Cerebrospinal fluid biomarkers did not change for insulin-treated participants as a group, but, in exploratory analyses, changes in memory and function were associated with changes in the AB42 level and in the tau protein-to-AB42 ratio in cerebrospinal fluid. Placebo-assigned participants showed decreased fludeoxyglucose F 18 uptake in the parietotemporal, frontal, precuneus, and cuneus regions and insulin-minimized progression. No treatment-related severe adverse events occurred.


According to the authors, these results support longer trials of intranasal insulin therapy for patients with amnestic mild cognitive impairment and patients with AD.

Hospitalizations Increase for Alcohol and Drug Overdoses



If we really want to reduce health care costs, we must address many of our self-inflicted diseases.


According to an article published in the Journal of Studies on Alcohol and Drugs (2011;72:774–786), hospitalizations for alcohol and drug overdoses – alone or in combination – increased dramatically among 18- to 24-year-olds between 1999 and 2008. Over the 10-year study period, hospitalizations among 18-24-year-olds increased by 25% for alcohol overdoses; 56% for drug overdoses; and 76% for combined alcohol and drug overdoses. The study examined hospitalization data from the Nationwide Inpatient Sample, a project of the U.S. Agency for Healthcare Research and Quality designed to approximate a 20% sample of U.S. community hospitals.


According to the authors, in 2008, 1 out of 3 hospitalizations for overdoses in young adults involved excessive consumption of alcohol and that alcohol overdoses alone caused 29,000 hospitalizations, combined alcohol and other drug overdoses caused 29,000, and drug overdoses alone caused another 114,000. The cost of these hospitalizations now exceeds $1.2 billion per year just for 18-24-year-olds.


According to the authors, this is a growing problem for those outside of the 18-24 age range, as well as among the entire population 18 and older, 1.6 million people were hospitalized for overdoses in 2008, at a cost of $15.5 billion, and half of these hospitalizations involved alcohol overdoses.


The current study also showed an increase of 122% in the rate of poisonings from prescription opioid pain medications and related narcotics among 18-24 year olds. An alcohol overdose was present in 1 of 5 poisonings on these medications.


The authors noted that the steep rise in combined alcohol and drug overdoses highlights the significant risk and growing threat to public health of combining alcohol with other substances, including prescription medications. They call for stronger efforts to educate medical practitioners and the general public about the dangers of excessive alcohol consumption alone or in combination with other drugs.

Gestational Age at Birth and Mortality in Young Adulthood



Preterm birth is the leading cause of infant mortality in developed countries, but the association between gestational age at birth and mortality in adulthood remains unknown. As a result, a study published in the Journal of the American Medical Association (2011;306:1233-1240) was performed to examine the association between gestational age at birth and mortality in young adulthood.


For the study, data were derived from the national cohort study of 674,820 individuals born as singletons in Sweden in 1973 through 1979 who survived to age 1 year, including 27,979 born preterm (gestational age <37 weeks), followed up to 2008 (ages 29-36 years). The main outcome measures were all-cause and cause-specific mortality.


A total of 7,095 deaths occurred in 20.8 million person-years of follow-up. Among individuals still alive at the beginning of each age range, a strong inverse association was found between gestational age at birth and mortality in early childhood (ages 1-5 years: adjusted hazard ratio [aHR] for each additional week of gestation, 0.92; P <0.001), which disappeared in late childhood (ages 6-12 years: aHR, 0.99) and adolescence (ages 13-17 years: aHR, 0.99) and then reappeared in young adulthood (ages 18-36 years: aHR, 0.96; P <0.001). In young adulthood, mortality rates (per 1000 person-years) by gestational age at birth were 0.94 for 22 to 27 weeks, 0.86 for 28 to 33 weeks, 0.65 for 34 to 36 weeks, 0.46 for 37 to 42 weeks (full-term), and 0.54 for 43 or more weeks. Preterm birth was associated with increased mortality in young adulthood even among individuals born late preterm (34-36 weeks, aHR, 1.31; P <0.001), relative to those born full-term. In young adulthood, gestational age at birth had the strongest inverse association with mortality from congenital anomalies and respiratory, endocrine, and cardiovascular disorders and was not associated with mortality from neurological disorders, cancer, or injury.


According to the authors, after excluding earlier deaths, low gestational age at birth was independently associated with increased mortality in early childhood and young adulthood.

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



FDA Approves Soliris for Atypical Hemolytic Uremic Syndrome (aHUS)



The FDA has approved Soliris (eculizumab; Alexion Pharmaceuticals) for the treatment of patients with atypical Hemolytic Uremic Syndrome (aHUS), a rare and chronic blood disease that can lead to kidney (renal) failure and is also associated with increased risk of death and stroke. aHUS accounts for 5-10% of all cases of aHUS. The disease disproportionately affects children.


Soliris is a targeted therapy that works by inhibiting proteins that play a role in aHUS. The FDA first approved Soliris in March 2007 to treat paroxysmal nocturnal hemoglobinuria (PNH), a rare type of blood disorder that can lead to disability and premature death. Soliris is classified as an orphan drug. Orphan drugs are those that demonstrate promise for the diagnosis and/or treatment of rare diseases or conditions.


There are no other FDA-approved treatments for aHUS, and the safety and effectiveness of current standard treatment, plasma therapy (plasma exchange or fresh frozen plasma infusion), have not been studied in well controlled trials. According to FDA, this is the first approval of a drug for treating this life-threatening disease, and the first approval for use of Soliris in children, and that this approval underscores how an increased understanding of the biology of a disease and of how a drug interacts with that process can expedite drug development.”


Soliris’ safety and effectiveness were established in two single-arm trials in 37 adults and adolescent patients with aHUS and one retrospective study in 19 pediatric patients and 11 adult patients with aHUS. Patients treated with Soliris in these studies experienced a favorable improvement in kidney function, including elimination of the requirement for dialysis in several patients that did not respond to plasma therapy. Patients treated with Soliris also exhibited improvement in platelet counts and other blood parameters that correlate with aHUS disease activity.


The most common side effects seen in patients treated with Soliris for aHUS included high blood pressure (hypertension), diarrhea, headache, anemia, vomiting, nausea, upper respiratory and urinary tract infections, and a decrease in white blood cells (leukopenia).


This new indication for Soliris is being approved with an extension of the existing Risk Evaluation and Mitigation Strategy (REMS), to inform health care professionals and patients about the known risk of life-threatening meningococcal infections. Soliris will continue to be available only through a restricted program, and prescribers must enroll in a registration program and provide a medication guide to patients who receive the drug.


Soliris was reviewed under the FDA’s priority review program, which provides for an expedited six-month review of drugs that may offer major advances in treatment or that provide a treatment when no adequate therapy exists. The therapy also is being approved under the FDA’s accelerated approval program, designed to provide patients with earlier access to promising new drugs followed by further studies to confirm the drug’s clinical benefit. The accelerated approval program allows the agency to approve a drug to treat a serious disease based on clinical data showing that the drug has an effect on an endpoint that is reasonably likely to predict a clinical benefit to patients, or on an effect on a clinical endpoint other than survival or irreversible morbidity.




Target Health Inc.
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