Orphan Drug Presentation at ILSI BIOMED Israel

Dr. Jules T. Mitchel, President of Target Health, will be presenting at a panel on Orphan Drugs and Devices, on Tuesday May 24, 2011, at the annual ILSI BIOMED conference at the David Intercontinental in Tel Aviv. Topics include: How the orphan drug/device regulation works and its features, Potential changes and Integration with the EMA. Please let us know if you will be at BIOMED.


Director of Operations

Target Health is continuing its search for a Director of Operations. The candidate should have a minimum of 10 years of experience in drug or device development, and either an MBA, PhD, or MD degree.



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 at:www.targethealth.com


Why Some Genes Are Silenced:

Clue to How Notes Are Played on the “Genetic Piano”


Dr. Kohzoh Mitsuya, of the School of Medicine at the University of Texas Health Science Center San Antonio (Credit: UT Health Science Center San Antonio)




Japanese and U.S. scientists in the young field of epigenetics have reported a rationale as to how specific 1) ___ are silenced and others are not. Because this effect can be reversed, it may be possible to devise therapies for cancer and other diseases using this information.


The NOVA U.S. public television program described epigenetics as “The Ghost In Your Genes.” It is the study of changes in gene expression that occur without changes in DNA sequence. Like keys on a piano, DNA is the static blueprint for all the proteins that cells produce. 2) ___ information provides additional dynamic or flexible instructions as to how, where and when the blueprint will be used. “It corresponds to a pianist playing a piece of music,” said Kohzoh Mitsuya, Ph.D., postdoctoral fellow in the School of Medicine at The University of Texas Health Science Center San Antonio.


The study by Dr. Mitsuya and colleagues is outlined in the May 13 issue of the journal Science. The team found that a small RNA pathway is required to establish an epigenetic modification – called DNA methylation – at a gene that codes for mammalian proteins. DNA methylation adds chemical tags called 3) ___ groups to specific genes, usually silencing their expression.


“DNA methylation marks are reversible, so there is great interest in devising therapeutic strategies, for instance in cancer biology, to epigenetically reactivate silenced 4) ___-suppressor genes or inactivate specific oncogenes in human cancer cells,” Dr. Mitsuya said. The lead author is Toshiaki Watanabe, Ph.D., of the National Institute of Genetics in Japan and Yale University.


Beyond being reversible, DNA methylation is susceptible to 5) ___ influences. Many cancer biologists now agree that changes in DNA methylation might be as important as genetic mutations in causing cancer. There are far more epigenetic changes than genetic changes found in the majority of cancers, and research into epigenetics is proving to be important to understanding cancer 6) ___.


“It is critical to identify the entire complement of factors that affect gene 7) ___,” Dr. Mitsuya said.


The researchers compared a group of 8) ___ mice with a group lacking the small RNA species. The team found that DNA methylation was markedly reduced at one of four genes tested in the small RNA-deficient mice. “This is the first demonstration that small RNAs can act in this way,” Dr. Mitsuya said. “It shows how one note is played on the piano.”


Epigenetic activity is a previously unseen dimension of biology that may enable clearer detection of 9) ___, monitoring of progression and improved treatment, and may provide entirely new biomarkers of disease susceptibility. “The symphony has only just come into view,” Dr. Mitsuya said. “We can hear it, but we need to learn how all the parts are being played.”



ANSWERS: 1) genes; 2) Epigenetic; 3) methyl; 4) tumor; 5) environmental; 6) biology; 7) silencing; 8) normal; 9) disease

Edward Augustus Holyoke MD (1728-1829) – One Hundred Years of American History Seen Through the Life of Dr. Holyoke


From: Harvard’s Biography of Edward Augustus Holyoke (1728-1829)


The Holyoke Award is named after Edward Holyoke, the eminent 18th century Salem physician, whose professional life had a tremendous impact on the health and well-being of his community. Holyoke received a medical degree from Harvard College and was the first president of the Massachusetts Medical Society. Holyoke practiced medicine in Salem for 80 years, averaging 11 house calls a day and delivering 100 babies a year. It was said that there was hardly a single home in Salem that he did not visit professionally. When he died at the age of 100, all of Salem’s church bells tolled and a great crowd gathered at the North Church to honor him.


In Aug. 21, 1828, on the occasion of his 100th birthday, many of Salem’s most important citizens gathered at the Essex House to pay tribute to one of the town’s most beloved citizens, Dr. Edward Augustus Holyoke. The highlight of the event was a toast offered by the honoree to his beloved Massachusetts Medical Society.


Edward Augustus Holyoke entered Harvard University at the age of 14 and graduated in the class of 1746 with an AM degree. He briefly taught in Lexington and Roxbury, but then he moved to his mother’s hometown of Ipswich to study medicine under the esteemed physician, Col. Thomas Perry. When his two-year apprenticeship ended in 1749, Holyoke settled in Salem and opened a practice. After a shaky start, Holyoke began attracting patients locally and in communities as far away as Methuen and Cape Ann. Over 80 years as a physician, traveling by horseback, chaise, or on foot, Holyoke would cover an estimated one-and-a-half-million miles and make approximately a quarter-of-a-million house calls. Holyoke was essentially a family physician. His practice is reputed to have been based on 4 drugs; mercury, antimony, opium and Peruvian bark. He also prescribed cold baths, and in obstetrical cases he was reluctant to use forceps.


From 1762 to 1817, 35 physicians apprenticed under him, among them Nathanial Walker Appleton, John Collins Warren and James Jackson. Holyoke remained dedicated to the study of medicine and new medical treatments. For 75 years he kept daily weather records in the hopes of finding scientific connections between local atmospheric conditions and specific diseases. While this venture proved unsuccessful, he made many other contributions to the field of medicine. For example, Holyoke was one of the first to make the connection between the use of pewter dishes and lead poisoning.

On November 18th, 1755, an earthquake hit the seacoast from Nova Scotia to Chesapeake Bay, causing extensive damage. Dr. Holyoke described it as follows: “At 4h. 15m. we were awakened by a greater earthquake than has ever been known in this country. Tops of chimneys and stone walls were thrown down, and clocks stopped by the shake. I thought of nothing less than being buried instantly in the ruins of the house.”


Holyoke’s open-mindedness made him a pioneer in the treatment and prevention of smallpox. When an epidemic hit the Salem area in 1777, Holyoke, after first making out his will, allowed himself to be inoculated. Fortunately, he survived the highly controversial treatment. The success of this treatment made Holyoke a convert / early adaptor of smallpox treatment, and he inoculated 600 of his own patients, losing only two.


After 1781, Holyoke was singled out for many honors, one of which was to organize the Massachusetts Medical Society. He served for a time as the organization’s president and was a frequent contributor to its publication, now the New England Journal of Medicine. In 1783, he was awarded the first M.D. degree ever given by the Harvard Medical School.


During a measles epidemic in 1787 Holyoke is said to have made over 100 professional calls on each of several days. The records of his practice showed that for more than 75 years Holyoke averaged 11 calls a day. His fees were low and he never pressed for payment. Throughout his life Holyoke was interested in science, especially astronomy, meteorology and physical science. He kept careful records of weather and temperatures, appearance of comets, aurora borealis, eclipses, earthquakes, etc. At one time he tried to correlate the weather with prevailing diseases or at another he invented an “American thermometer” that was based on the freezing points of mercury and water.


Holyoke was so determined to understand diseases that he even performed autopsies on the bodies of his own children. Holyoke’s interests were not limited to science and medicine. He was a founder of both the Social and Philosophical libraries in Salem, and was a driving force in the merger of these two institutions into the Salem Athenaeum in 1810. He was also an incorporator of the Essex Historical Society, later the Essex Institute, in 1821. When the American Academy of Arts and Sciences was formed in 1790 for the encouragement and dissemination of knowledge, Holyoke joined the likes of George Washington and Benjamin Franklin as a charter member. He later served as the academy’s president for six years.


Holyoke, a near vegetarian who liked his liquor and tobacco, He claimed his secret for longevity was “moderation, avoid pork, eat all fruits in their season and drink not more than a pint a day – a mixture of 2 part parts good West India rum, 3 parts cider and nine or ten parts water.”


When health began to fail him during the winter of 1828-1829, Holyoke recorded his symptoms and reached his own diagnostic conclusion, which disputed his own physician’s diagnosis. After his death and in accordance with his instructions, his colleagues performed a complete post-mortem and found that Holyoke’s diagnosis had been correct.

Tired Neurons Caught Nodding Off In Sleep-Deprived Rats


According to an article published online in the April 28, 2011 issue of the journal Nature, a new study in rats is shedding light on how sleep-deprived lifestyles might impair functioning without people realizing it. The more rats are sleep-deprived, the more some of their neurons take “catnaps” – with consequent declines in task performance. Even though the animals are awake and active, brainwave measures reveal that scattered groups of neurons in the thinking part of their brain, or cortex, are briefly falling asleep.


“Such tired neurons in an awake brain may be responsible for the attention lapses, poor judgment, mistake-proneness and irritability that we experience when we haven’t had enough sleep, yet don’t feel particularly sleepy,” explained Giulio Tononi, M.D., Ph.D., of the University of Wisconsin-Madison.


Previous studies had hinted at such local snoozing with prolonged wakefulness. Yet little was known about how underlying neuronal activity might be changing. For the study, the authors tracked electrical activity at multiple sites in the cortex as they kept rats awake for several hours. To stimulate the rats, novel objects were put into their cages such as colorful balls, boxes, tubes and odorous nesting material from other rats. The sleepier the rats got, more subsets of cortex neurons switched off, seemingly randomly, in various localities. These tired neurons’ electrical profiles resembled those of neurons throughout the cortex during NREM or slow wave sleep. Yet, the rats’ overall EEG, a measure of brain electrical activity at the scalp, confirmed that they were awake, as did their behavior.


However subtle, having tired neurons did interfere with task performance. If neurons switched off in the motor cortex within a split second before a rat tried to reach for a sugar pellet, it decreased its likelihood of success by 37.5%. And the overall number of such misses increased significantly with prolonged wakefulness. This suggests that tired neurons, and accompanying increases in slow wave activity, might help to account for the impaired performance of sleep-deprived people who may seem behaviorally and subjectively awake.


Subsets of neurons going offline with longer wakefulness is, in many ways, the mirror image of progressive changes that occur during recovery sleep following a period of sleep deprivation. The authors suggest that both serve to maintain equilibrium as part of the compensatory mechanisms that regulate sleep need. Just as sleep deprivation produces a brain-wide state of instability, it may also trigger local instability in the cortex, possibly by depleting levels of brain chemical messengers. So, tired neurons might nod off as part of an energy-saving or restorative process for overloaded neuronal connections.


“Research suggests that sleep deprivation during adolescence may have adverse emotional and cognitive consequences that could affect brain development,” noted NIMH Director Thomas R. Insel, M.D. “The broader line of studies to which this belongs, are, in part, considering changes in sleep patterns of the developing brain as a potential index to the health of neural connections that can begin to go awry during the critical transition from childhood to the teen years.”

Vitamin E Helps Diminish a Type of Fatty Liver Disease in Children


Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease among U.S. children. Most children with fatty liver disease are overweight and resistant to insulin, a critical hormone that regulates energy. Boys are more likely affected than girls, as are Hispanic children compared to African-Americans and whites. NAFLD ranges in severity from steatosis (fat in the liver without injury) to nonalcoholic steatohepatitis or NASH (fat, inflammation, and liver damage). Fatty liver increases a child’s risk of developing heart disease and liver cirrhosis. The only way to distinguish NASH from other forms of fatty liver disease is with a liver biopsy. Weight loss may reverse the disease in some children, but other than dietary advice, there are no specific treatments. Excess fat in the liver is believed to cause injury by increasing levels of oxidants, compounds that damage cells.


A previous study found vitamin E effective in some adults with NAFLD. As a result, a study published in the Journal of the American Medical Association (2011;305:1659-1668) was performed to determine whether children with NAFLD would improve from therapeutic intervention with vitamin E or metformin.


The Treatment of Nonalcoholic Fatty Liver Disease in Children (TONIC) trial studied whether vitamin E (an antioxidant) or metformin could improve fatty liver disease. The endpoint to measure success was either a sustained reduction in the liver enzyme alanine aminotransferase (ALT) or improvements in the liver as shown by biopsies. The study was a randomized, double-blind, double-dummy, placebo-controlled clinical trial conducted at 10 university clinical research centers in 173 patients (aged 8-17 years) with biopsy-confirmed NAFLD conducted between September 2005 and March 2010. Treatments included daily dosing of 800 IU of vitamin E (58 patients), 1000 mg of metformin (57 patients), or placebo (58 patients) for 96 weeks.


Using liver biopsies, results showed that after 96 weeks of treatment, 58% of the children on vitamin E no longer had NASH, compared to 41% of the children on metformin (a diabetes drug), and 28% on placebo. Vitamin E was better than placebo because it significantly reduced enlargement and death of liver cells.


Neither vitamin E nor metformin were significantly better than placebo in reducing ALT levels. Twenty-six percent of patients on vitamin E, 16% on metformin, and 17% of those on placebo had reduced liver enzyme levels. Interestingly, ALT levels improved more rapidly among patients on vitamin E (within six months) compared to those on placebo. The ALT levels among the children on placebo improved over the two years.

Propranolol for the Treatment of Ulcerated Infantile Hemangiomas


The Scottish scientist James W. Black successfully developed propranolol in the 1960s. In 1988, he was awarded the Nobel Prize in Medicine for this discovery. Propranolol was derived from the early β-adrenergic antagonists dichloroisoprenaline and pronethalol. The key structural modification, which was carried through to essentially all subsequent beta blockers, was the insertion of a methoxy bridge into the arylethanolamine structure of pronethalol thus greatly increasing the potency of the compound. This also apparently eliminated the carcinogenicity found with pronethalol in animal models.


An infantile hemangioma, or “strawberry mark,” is a very common type of birthmark made of blood vessels. Most hemangiomas are not visible at birth. They may at first only appear as a small bruise, scratch or a tiny red bump. Unlike other types of birthmarks, hemangiomas grow and change greatly during the first months of life. They may occur anywhere on the skin surface but are most common on the scalp, face and neck. All skin hemangiomas are seen by 6 months of age and can result in pain, infection, bleeding, scarring and interfere with sleeping or feeding, all of which may adversely affect the quality of life of the child and its family.


Management of ulcerated IH includes analgesia, wound care, and antibiotics, if required for secondary infection. Other treatment modalities include systemic corticosteroids, intralesional corticosteroids, flashlamp pulsed-dye laser therapy (FPDL), interferon-alfa, and vincristine. Complete wound healing may take almost 3 months with any treatment regimen.


The word “hemangioma” comes from the Greek haema (blood); angeio (vessel); and oma (tumor). Ulcerated infantile hemangiomas (IH) are a specific therapeutic challenge.


Propranolol, a very old, nonselective beta-blocker, was recently introduced as a novel treatment for IH. As a result, a study published in the Journal of the American Academy of Dermatology (2011; 64:827-832) was performed to evaluate the effects of propranolol in the management of ulcerated IH.


For the study, data were collected from the medical charts of patients treated from 2008 to 2009 and supplemented by information obtained from parents during targeted telephone interviews. Parents were informed that propranolol was prescribed on a compassionate basis and they gave consent for its use. Before starting propranolol, each child underwent echocardiography. Once the agreement of a pediatric cardiologist was obtained, the treating physician prescribed propranolol, 2 to 3 mg/kg per day in 2 or 3 divided doses. The dose was increased to a maximum of 3 mg/kg per day depending on the clinical response. Blood pressure and heart rate were monitored at least once monthly.


Thirty-three infants with propranolol-treated ulcerated IH were included in the analysis. The average time to complete ulceration healing was 4.3 weeks in 30 of 33 patients and was significantly faster for head-and-neck locations (P = .0354). The mean time to complete pain control was 14.5 days. Parents rated treatment as very effective for 27 of 31 patients and very well tolerated for 29 of 31 cases.


According to the authors, propranolol appears to be an effective and well-tolerated treatment for ulcerated IH.

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



Current Trends in FDA Inspections Assessing Clinical Trial Quality: An Analysis of CDER’s Experience



The following article was authored by Ann Meeker-O’Connell and Leslie K. Ball of FDA and published in the Food and Drug Law Institute April/May 2011. Please let us know if you would like a copy of the article.


Over the past five years, the Division of Scientific Investigations (DSI) has overseen approximately 480 on-site inspections of clinical investigators, clinical trial sponsors and contract research organizations (CRO) annually. Of these, approximately 70% were conducted as part of NDA or BLA review, with the remainder arising from complaints. Selection of sites for NDA and BLA related inspections is generally based upon a site’s importance to the data supporting an application, such as the number of subjects enrolled or the site’s relative contribution to study efficacy conclusions. Where an application relates to a new molecular entity, FDA generally inspects the sponsor in addition to the clinical investigator sites.


Recently, CDER has been piloting a risk-based clinical investigator site selection tool that permits quantitative evaluation of an array of factors that may indicate a higher risk of data integrity concerns. The DSI reviewer’s primary role during NDA and BLA review is to critically evaluate inspectional findings and their overall impact on site and study data integrity and human subject protections. When a field investigator observes conditions that are felt to constitute a regulatory violation, the field investigator will recommend an action, taking into consideration the nature of the inspectional findings, any actions that occurred following the findings and agency policy. DSI reviews the recommended action, determines whether is the action is appropriate and makes a final decision about the inspection classification. Depending on the nature of the violations, FDA may ultimately find that corrective action may be left to the establishment to take voluntarily (voluntary action indicated, or VAI). Alternatively, FDA may determine that regulatory and/or administrative sanctions are necessary to more immediately address significant objectionable conditions or practices and classify the inspection as OAI (official action indicated). OAI actions may range from issuance of a warning letter to pursuit of disqualification of a clinical investigator. In addition to reviewing the outcomes of individual inspections, DSI reviewers also consider whether and how inspectional findings inform FDA’s conclusions about the reliability of data in a marketing application.


The current study evaluated DSI’s compliance reviews completed during FY2010 and 1Q FY2011 for 104 new and supplemental marketing applications. In total, CIS memos for these applications covered 333 clinical investigator, 37 sponsor and 23 CRO inspections. Ninety five percent (95%) of inspections were classified as either No Action Indicated (51%), meaning that no objectionable conditions or practices were found, or as VAI (44%). However, in this time period, DSI also recommended the rejection of data submitted by sponsors for 13 of the 333 (4%) clinical investigators inspected. Eight of these 13 investigators conducted trials supporting the five applications described below, for which data integrity concerns led to delays in approval or resulted in an applicant receiving a complete response letter. The remaining four clinical investigators were each associated with a different marketing application. In these four cases, DSI recommended rejecting the clinical investigator’s data. DSI nonetheless did not recommend rejection of data for the entire study, as significant noncompliance appeared to be limited in scope and to have been identified and promptly addressed by the sponsors involved. As noted during the time period, data integrity concerns led to refusals to file, rejection of study data and/or a request for additional sponsor actions to demonstrate data reliability for five (4.8%) of the applications. Notably, for two of these five applications, concerns about trial data integrity came from sponsor and CRO data management practices and not from clinical investigator site inspections. In the case of one application, FDA’s clinical reviewers noticed numerous discrepancies between case report forms and data listings when the application was first received, raising questions about data entry quality control. In the other, FDA became concerned about data integrity during an on-site inspection of CRO records related to database changes after the initial database lock and study unblinding.


Representative examples of findings include:


  • Repeated failure to complete or document study procedures and data necessary to interpret a primary endpoint, such as not conducting a protocol-required efficacy follow-up visit for any enrolled subject;
  • Widespread discrepancies and omissions in study records related to investigational product administration, making it impossible to confirm enrolled subjects received the assigned investigational product in accordance with the protocol-defined dosing regimen;
  • Pervasive discrepancies between an investigator’s records and primary endpoint data reported by the investigator to the sponsor;
  • Systemic underreporting of adverse events, bringing into question the completeness of data on which safety conclusions were based and
  • Repeated enrollment of study subjects in violation of key eligibility criteria designed to exclude subjects for whom participation posed significant risk.


In most of the 20% of OAI cases in which DSI did not recommend data rejection, the regulatory violations that led to the OAI classification did not appear to undermine data integrity. For example, in one instance, a clinical investigator initiated study conduct prior to obtaining initial Institutional Review Board approval, and in another, a sponsor-investigator undertook a study prior to filing an IND. However, for two investigators for whom data were deemed reliable, regulatory violations would have led to a recommendation not for rejection but for timely corrective actions implemented by the investigators.


According to the authors, while there is a tendency to focus here on inspectional outcomes, an oversight model premised largely on retrospectively identifying critical errors may be outmoded and inefficient. Instead, an approach that builds quality into clinical trial design, conduct and oversight may be much better suited to the scale, global nature and complexity of the current drug development environment and to preventing the rare but costly cases in which clinical trial quality issues impact application approval. Such an approach recognizes that different aspects of clinical trials may present a higher compliance risk and permits both clinical trial sponsors and FDA to focus our efforts on activities that present a greater risk to data integrity and human subjects protection.


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).

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