First Direct Data Entry Phase 2 Study Completed – VIRTUALLY NO PAPER USED

 

 

 

Target Health is pleased to announce that it has completed its first Phase 2 direct data entry (DDE) clinical trial. A second Phase 2 study will be initiated in September and a Phase 3 program in January. An NDA submission utilizing Target Health’s full paperless software suite is planned for Q4 2012.

 

The Phase 2 study took place at a single site study with 20 patients, all treated on the same day on 6 separate days, and a total of 11 study visits (220 total patient visits). The study utilized Target e*CRF® for data entry and Target e*CTR® (eClinical Trial Record; patent pending) as the source record. Target e*CTR is controlled by the clinical site thus compliant with FDA and EMA Guidances. Except for minimal patient information coming out of the electronic health record at the site, the vast majority of the data were entered at the time of the office visit. Not only were data entered in real time, but we were able to monitor the patient record in real time.

 

From the site’s perspective, once the patient left the office, there was nothing to do except answer a few queries. From the Sponsor’s perspective, monitoring was done in house at Target Health and there was no need to do any onsite monitoring during the study. The monitor was at the site at the time of the initial patient visit to review the informed consent forms, do some risk-based SDV of certain paper records, and to assure that the site personnel understood and were following the protocol. All patient records were monitored in-house within 1 hour of the office visit. The site informed us that they saved 70 hours of data entry time and the total monitoring time spent was 10 hours over a 10 week period, with no travel time or travel costs.

 

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.

Faster Healing for Severe Fractures

 

New bone: An x-ray image of a patient who had a leg lengthened using the new surgical method. This image was taken after six months, showing a healed bone. Credit: Ulf Knothe

 

 

 

Slicing and dicing: This illustration shows how a section of bone with a tumor (very top) can be removed (A), leaving a gap in the bone. The periosteum is then cut and peeled back (B), but remains intact. The bone underneath is then moved down (C) to fill the gap, and the periosteum is sutured around the area where the bone was removed. Credit: Cleveland Clinic Center for Medical Art & Photography

 

 

 

A simple method uses stem cells from bone tissue to repair serious injuries quickly and cheaply. This new surgical procedure can repair severe bone injuries and defects more quickly and simply than current methods, which include bone-grafting operations and lengthening procedures that involve inserting pins through the skin to pull 1) ___ together. The new technique makes use of a thin tissue called the periosteum, which lines the outer surface of all bones and contains stem 2) ___ that develop into bone to repair damage. To repair major bone breaks, or repair serious defects, the researchers use the periosteum as a sleeve placed around a missing section of bone to encourage bone 3) ___. For cases where there is not enough periosteum, the researchers have developed an artificial membrane as a substitute.

 

Melissa Knothe Tate, a professor of biomedical engineering at Case Western Reserve University in Cleveland, and her husband, Ulf Knothe, an orthopedic surgeon at the Cleveland Clinic, have successfully tested their method on a wheelchair-bound patient who needed surgery to lengthen one of her 4) ___. They’ve also successfully tested it on sheep. The researchers presented their work at the Orthopedic Research Society meeting in New Orleans.

 

In the new procedure, the researchers made a small vertical incision in the periosteum near to where a large piece of bone was missing after the leg had been lengthened. They then peeled the periosteum back, so that it remained attached to the blood vessels on the outside, and cut away a piece of bone beneath, which was then used to plug the large gap in the leg bone. The periosteum was sutured closed, forming a sleeve around the section from which the bone was removed. The gap was repaired by the transplanted segment of bone while cells from the sutured 5) ___ infiltrated the space below it and turned into new bone. The patient saw new bone growth one month after 6) ___. Such a defect would normally not heal without more serious surgery. One of the most common methods for treating a severe bone injury is to take bone from a non-weight-bearing area like the hip and graft it onto the injured site, but that can leave the site the bone was taken from at risk of a fracture. Jennifer Elisseeff, a biomedical engineer at Johns Hopkins University, said that very little can be done to fix large 7) ___ in bone, but adds that the new technique “will have a significant effect for healing fractures.”

 

Norman Marcus, an orthopedic surgeon at the Virginia Cartilage Institute, in Springfield, VA, says artificial treatments fall into two categories: structural and growth-related. Structural products, typically called bone fillers, can be made of items like coral and calcium phosphate. Growth-related products, which are usually in the form of powders and gels, are used to stimulate bone 8) ___. While the growth promoters are more effective, they are expensive, says Marcus.

 

The researchers have also created an artificial periosteum sleeve, which they tested in sheep, for bone injuries where there is not enough tissue available. The artificial membrane was seeded with collagen; a mixture of collagen and periosteal cells taken from a particular sheep; or pieces of periosteum from the patient’s surrounding bone. The researchers wrapped the sleeve around the injured area and sewed it on like a patch. They found that the sheep given the periosteum alone experienced the fastest repair, with new bone growth two to three weeks after surgery.

 

The work “combines tissue engineering approaches with surgical intervention and leverages the natural ability for repair,” says Elisseeff. One problem is that stem cells can differentiate into different things like tendons, cartilage, or bone, says Marcus. The researchers showed that the stem cells in the periosteum were coaxed into becoming bone by mechanical stress. For instance, in the sheep experiments, the mechanical cues happen naturally when the sheep shift their 9) ___.

 

“There are lots of experimental techniques but few clinical methods, and if this has been successful in patients, that is where the real breakthrough will be,” says Farshid Guilak, a professor of orthopedic surgery and director of the Orthopaedic Bioengineering Laboratory at Duke University Medical Center. “This is very important progress,” adds Yunzhi Yang, an assistant professor at Houston Biomaterials Research Center at the University of Texas Health Science Center in Houston. Knothe Tate says the plan is to license the technology to companies by the end of the year, and says there are a couple of “major players” interested. “We want to provide a cheap alternative that can be widely used in the field,” she says. Source: MIT Technology Review

 

ANSWERS: 1) bones; 2) cells; 3) regrowth; 4) legs; 5) periosteum; 6) surgery; 7) gaps; 8) growth; 9) weight

Aspirin

 

Old advertisement for Bayer pharmaceuticals, uses pre-1904 company logo. Advertisement for Aspirin Heroin, Lycetol and Salophen

 

 

 

Plant extracts, including willow bark and spiraea, of which salicylic acid was the active ingredient, had been known to help alleviate headaches, pains and fevers since antiquity. The father of modern medicine, Hippocrates left historical records describing the use of powder made from the bark and leaves of the willow tree to help these symptoms.

 

A French chemist, Charles Frederic Gerhardt, was the first to prepare acetylsalicylic acid in 1853. In the course of his work on the synthesis and properties of various acid anhydrides, he mixed acetyl chloride with a sodium salt of salicylic acid (sodium salicylate). A vigorous reaction ensued, and the resulting melt soon solidified. Since no structural theory existed at that time, Gerhardt called the compound he obtained “salicylic-acetic anhydride” (wasserfreie Salicylsaure-Essigsaeure). This preparation was one of the many reactions Gerhardt conducted for his paper on anhydrides and he did not pursue it further.

 

Six years later, in 1859, von Gilm obtained analytically pure acetylsalicylic acid (which he called acetylierte Salicylsaeure, acetylated salicylic acid) by a reaction of salicylic acid and acetyl chloride. In 1869, Schroeder, Prinzhorn and Kraut repeated both Gerhardt’s (from sodium salicylate) and von Gilm’s (from salicylic acid) syntheses and concluded both reactions gave the same compound – acetylsalicylic acid. They were first to assign to it the correct structure with the acetyl group connected to the phenolic oxygen.

 

1923 Advertisement

 

 

 

In 1897, chemists working at Bayer AG produced a synthetically altered version of salicin, derived from the species, which caused less digestive upset than pure salicylic acid. By 1899, Bayer was selling it worldwide. The new drug, formally acetylsalicylic acid, was named Aspirin by Bayer AG after the old botanical name for meadowsweet, Spiraea ulmaria. The name Aspirin is derived from acetyl and spirsaeure, an old German name for salicylic acid. The popularity of aspirin grew over the first half of the 20th century, spurred by its supposed effectiveness in the wake of the Spanish flu pandemic of 1918. However, recent research suggests the high death toll of the 1918 flu was partly due to aspirin, as the doses used at times can lead to toxicity, fluid in the lungs, and, in some cases, contribute to secondary bacterial infections and mortality. Aspirin’s profitability led to fierce competition and the proliferation of aspirin brands and products, especially after the American patent held by Bayer expired in 1917.

 

The popularity of aspirin declined after the market releases of paracetamol (acetaminophen) in 1956 and ibuprofen in 1969. In the 1960s and 1970s, John Vane and others disco established aspirin’s efficacy as an anticlotting agent that reduces the risk of clotting diseases. Aspirin sales revived considerably in the last decades of the 20th century, and remain strong in the 21st century, because of its widespread use as a preventive treatment for heart attacks and strokes.

 

As part of war reparations specified in the 1919 Treaty of Versailles following Germany’s surrender after World War I, Aspirin (along with heroin) lost its status as a registered trademark in France, Russia, the United Kingdom, and the United States, where it became a generic name. Today, “aspirin” is a generic word in Australia, France, India, Ireland, New Zealand, Pakistan, Jamaica, the Philippines, South Africa, United Kingdom and the United States. Aspirin, with a capital “A”, remains a registered trademark of Bayer in Germany, Canada, Mexico, and in over 80 other countries, where the trademark is owned by Bayer.

GENETICS

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Gene Variant Identified in Proteus Syndrome – Molecular Insight May Confirm Cause Of The Elephant Man’s Severe Disfigurement

 

 

 

Proteus syndrome gained wide public attention in 1980, through the movie “The Elephant Man,” about a 19th century Londoner, Joseph Merrick, who experts believe may have suffered from the disease. Physicians named the condition for the Greek god who could transform his shape. There are fewer than 500 people with the disease in the developed world. Until now, clinical diagnosis has been based on observation of patient features. Besides overgrowth of limbs, the condition is characterized by a variety of skin lesions and thickening of the soles of the feet. Some patients have neurological complications, such as mental retardation, seizures and vision loss. The affected newborn appears normal, but symptoms arise in the child’s first two years.

 

According to an article that appeared in the July 27, 2011, early online edition of the New England Journal of Medicine, the genetic mutation has been identified that causes Proteus syndrome. The team was led by researchers at the National Human Genome Research Institute (NHGRI), part of the National Institutes of Health. The study found that a point mutation, a single-letter misspelling in the DNA of the genetic code in the AKT1 gene activates the sporadic tissue growth characteristic of Proteus syndrome. Unlike inherited disease-causing mutations, the gene variant that triggers Proteus occurs spontaneously in each affected individual during embryonic development. The severity of the disease depends on the timing during embryonic development that the genetic mistake occurs in a single cell and in which part of the developing organism. Only the cells that descend from the cell with the original AKT1 gene mutation display the hallmarks of the disease, leaving the individual with a mixture of normal and mutated cells.

 

To find the single-letter misspelling among the 3 billion letters that make up the human genome, the researchers performed whole-exome sequencing on the DNA of seven patients with Proteus syndrome. Whole-exome sequencing determines the sequence of letters that make up the 1 to 2 percent of the genome that contains protein-coding genes. The research team then analyzed more than 20 additional affected individuals, finding the same gene variant in DNA in more than 90% of these individuals. The team suspects that the three individuals so far negative for the mutation may actually have the mutation at low levels or in different tissues than those sampled in the initial biopsy. By contrast, the variant is never found in unaffected people, including a random study population of more than 400 individuals and in thousands of DNA sequences maintained in public genome research databases.

 

As follow up to the current study, NHGRI researchers plan to test DNA from the skeleton of Joseph Merrick to determine whether Proteus syndrome caused his dramatic disfigurement. Merrick gained celebrity – and for a time earned his livelihood in England and Europe – by being displayed in human novelty exhibitions as the Elephant Man. He died in 1890 at the age of 27 in London Hospital, now the Royal London Hospital, where he resided at the end of his life. The hospital preserved his skeleton in its pathology collection, providing modern researchers a chance to test his century-old DNA.

 

Diagnosing Merrick will be no simple study. Because of the way the mutation occurs during embryonic development, the NHGRI-led team found that the gene variant of Proteus syndrome occurs in only a subset of the body’s cells rather than in every cell, a condition called a genetic mosaicism. There are only a small number of known mosaic disorders in which an individual’s cells have a different genetic composition from one another. Essentially, the person develops more than one genome. Since only a subset of the body’s cells harbor the mutation, it is possible that during a medical biopsy, in which bits of tissue are cut out for analysis, the diagnosis may be missed because only normal cells are sampled.

Effect of Age on Response to Amblyopia Treatment in Children

 

 

 

Amblyopia, or “lazy eye,” is the loss of one eye’s ability to see details. It is the most common cause of vision problems in children. Amblyopia occurs when the nerve pathway from one eye to the brain does not develop during childhood. This occurs because the abnormal eye sends a blurred image or the wrong image to the brain. This confuses the brain, and the brain may learn to ignore the image from the weaker eye. Strabismus is the most common cause of amblyopia and there is often a family history of this condition.

 

According to an article published online in the Archives of Ophthalmology (11 July 2011), a study was performed to determine whether age at initiation of treatment for amblyopia influences the response among children 3 to less than 13 years of age with unilateral amblyopia who have 20/40 to 20/400 amblyopic eye visual acuity.

 

A meta-analysis of individual subject data from 4 recently completed randomized amblyopia treatment trials was performed to evaluate the relationship between age and improvement in logMAR amblyopic eye visual acuity. Analyses were adjusted for baseline amblyopic eye visual acuity, spherical equivalent refractive error in the amblyopic eye, type of amblyopia, prior amblyopia treatment, study treatment, and protocol. Because there was a nonlinear relationship between age and improvement in amblyopic eye visual acuity, age was categorized by 3 to <5 years, 5 to <7 years, and 7 to <13 years.

 

Results showed that children from 7 to less than 13 years of age were significantly less responsive to treatment than were younger age groups for moderate and severe amblyopia (P < .04 for all 4 comparisons). There was no difference in treatment response between children 3 to less than 5 years of age and children 5 to less than 7 years of age for moderate amblyopia (P = .67), but there was a suggestion of greater responsiveness in children 3 to less than 5 years of age compared with children 5 to less than 7 years of age for severe amblyopia (P = .09).

 

According to the authors, amblyopia is more responsive to treatment among children younger than 7 years of age, although the average treatment response is smaller in children 7 to less than 13 years of age, some children show a marked response to treatment.

ONCOLOGY

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Depression and Leukocyte Telomere Length in Patients with Coronary Heart Disease

 

 

 

A telomere is a region of repetitive DNA sequences at the end of a chromosome, which protects the end of the chromosome from deterioration or from fusion with neighboring chromosomes. Its name is derived from the Greek nouns telos “end” and mers “part”. The telomere regions deter the degradation of genes near the ends of chromosomes by allowing for the shortening of chromosome ends, which necessarily occurs during chromosome replication. Over time, due to each cell division, the telomere ends do become shorter.

 

Shortened telomere length has been associated with mortality in patients with coronary heart disease (CHD) and is considered as an emerging marker of biologic age. Whether depression is associated with telomere length or trajectory has not been evaluated in patients with CHD. As a result, a prospective cohort study, published online in Psychosomatic Medicine (19 May 2011), measured leukocyte telomere length in 952 participants with stable CHD at baseline and in 608 of these participants after 5 years of follow-up. The presence of major depressive disorder in the past month was assessed using the computerized diagnostic interview schedule at baseline. The study used linear and logistic regression models to evaluate the association of depression with baseline and 5-year change in leukocyte telomere length.

 

Results showed that of the 952 participants, 206 (22%) had major depression at baseline. After the adjustment for age and gender, the patients with current major depressive disorder had shorter baseline telomere length than those without depression (mean = 0.86 versus 0.90; p = .02). This association was similar (but no longer statistically significant) after adjustment for body mass index, smoking, diabetes, left ventricular ejection fraction, statin use, antidepressant use, physical inactivity, and anxiety (0.85 versus 0.89; p = .06). Depression was not predictive of 5-year change in telomere length after adjustment for the mentioned covariates and baseline telomere length.

 

According to the authors, depression is associated with reduced leukocyte telomere length in patients with CHD but does not predict 5-year change in telomere length. The authors added that future research is necessary to elucidate the potential mechanisms underlying the association between depression and telomere length.

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

 

 

 

HHS Announces Proposal to Improve Rules Protecting Human Research Subjects

 

 

 

The U.S. Department of Health and Human Services has announced that the federal government is contemplating various ways of enhancing the regulations overseeing research on human subjects. Before making changes to the regulations – which have been in place since 1991and are often referred to as the Common Rule – the government is seeking the public’s input on an array of issues related to the ethics, safety, and oversight of human research. The changes under consideration can be found in an Advance Notice of Proposed Rulemaking (ANPRM), Human Subjects Research Protections: Enhancing Protections for Research Subjects and Reducing Burden, Delay, and Ambiguity for Investigators, published in the July 25 Federal Register. The proposed changes are designed to strengthen protections for human research subjects.

 

The current regulations governing human subject research were developed years ago when research was predominantly conducted at universities, colleges, and medical institutions, and each study generally took place at only a single site. Expansion of human subject research into many new scientific disciplines and venues and an increase in multi-site studies have highlighted ambiguities in the current rules and have led to questions about whether the current regulatory framework is effectively keeping up with the needs of researchers and research subjects.

 

Revisions to the current regulations are now being considered because HHS believes these changes will strengthen protections for research subjects in a number of important ways.

 

Comment is sought on the following:

 

  1. Revising the existing risk-based framework to more accurately calibrate the level of review to the level of risk.
  2. Using a single Institutional Review Board review for all domestic sites of multi-site studies.
  3. Updating the forms and processes used for informed consent.
  4. Establishing mandatory data security and information protection standards for all studies involving identifiable or potentially identifiable data.
  5. Implementing a systematic approach to the collection and analysis of data on unanticipated problems and adverse events across all trials to harmonize the complicated array of definitions and reporting requirements, and to make the collection of data more efficient.
  6. Extending federal regulatory protections to apply to all research conducted at U.S. institutions receiving funding from the Common Rule agencies.
  7. Providing uniform guidance on federal regulations.

 

The public’s input on these matters will be critically important to the government’s efforts to ensure that regulations keep up with today’s changing research environment, and will be considered by HHS as it develops new proposed rules, which will also be made public for comment.

 

To view the ANPRM, please visit http://www.hhs.gov/ohrp.

 

To submit a comment, visit http://www.regulations.gov, enter the above ID number, and click on “Submit a Comment.“

 

For additional information about the changes under consideration, visit http://www.hhs.gov/ohrp/humansubjects/anprm2011page.html.

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).

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.

 


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