New Publication: Monitoring the Quality of Conduct of Clinical Trials: A Survey of Monitoring Practices


Target Health is pleased to announce the publication of an article in Clinical Trials (2011;8:342-349) entitled: “Monitoring the quality of conduct of clinical trials: a survey of current practices.” The article was co-authored with our colleagues from FDA, Pfizer, Roche, BMS, Duke Translational Medicine Institute, Training Extension/Pastor Consulting, Inc. and Alquest, LLC.


The purpose of this project was to describe current methods of monitoring clinical trials and to explore the rationale for the use of those methods. Based on the creative input from the survey development team, consisting of Joan Harley, Cynthia Kleppinger, Cynthia Zacharias and Jules Mitchel, and critical input from members of the CTTI Steering and Executive Committees, Target Health’s Application Development Department programmed an electronic survey of known monitoring practices. The survey was sent to over 200 organizations involved in conducting clinical research and collected information on institutional demographics, methods of overall study oversight, use of risk-based monitoring and factors that influence assessments of risk. Details on quality assurance and monitoring practices were also collected. Based on the results of the survey, this esteemed group of authors concluded that the findings underscore the necessity of research to provide an evidence base for monitoring practice.


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



Stem Cells Restore Cognitive Abilities Impaired by Brain Cancer Treatment


UCI researcher Charles Limoli found that nearly half of the engrafted stem cells turned into cells that support neurons. (Credit: Steve Zylius / University Communications)




Human 1) ___ stem cells are capable of helping people regain learning and memory abilities lost due to radiation treatment for brain tumors, a UC Irvine study suggests. Research with rats found that stem 2) ___ transplanted two days after cranial irradiation restored cognitive function, as measured in one- and four-month assessments. In contrast, irradiated rats not treated with stem cells showed no 3) ___ improvement. “Our findings provide solid evidence that such cells can be used to reverse radiation-induced damage of healthy tissue in the 4) ___,” said Charles Limoli, a UCI radiation oncology professor.


Study results appear in the July 15 issue of Cancer Research, a journal of the American Association for Cancer Research.


Radiotherapy for brain tumors is limited by how well the surrounding tissue tolerates it. Patients receiving radiation at effective levels suffer varying degrees of learning and memory loss that can adversely affect their quality of 5) ___. “In almost every instance, people experience severe cognitive impairment that’s progressive and debilitating,” Limoli said. “Pediatric 6) ___ patients can experience a drop of up to three IQ points per year.”


For the UCI study, multipotent human neural 7) ___ cells were transplanted into the brains of rats that had undergone radiation treatment. They migrated throughout the hippocampus — a region known for the growth of new neurons — and developed into brain cells. Researchers assessed the rats one month and four months after transplantation, noting enhanced learning and 8) ___ abilities at both intervals. Additionally, they found that transplanting as few as 100,000 human neural stem cells was sufficient to improve cognition after cranial irradiation. Of cells surviving the process, about 15 percent turned into new neurons, while another 45 percent became astrocytes and oligodendrocytes – cells that support 9) ___ neurons.


Most notably, Limoli said, he and his colleagues discovered that about 11% of the engrafted cells expressed a behaviorally induced marker of learning, indicating the functional integration of those cells into memory circuits in the 10) ___. “This research suggests that stem cell therapies may one day be implemented in the clinic to provide relief to patients suffering from cognitive impairments incurred as a result of their cancer treatments,” Limoli said. “While much work remains, a clinical trial analyzing the safety of such approaches may be possible within a few years, most likely with patients afflicted with glioblastoma multiforme, a particularly aggressive and deadly form of brain cancer.”


ANSWERS: 1) neural; 2) cells; 3) cognitive; 4) brain; 5) life; 6) cancer; 7) stem; 8) memory; 9) cerebral; 10) hippocampus

Malaria – Part 1

The mosquito and the fly in this Baltic amber necklace are between 40 and 60 million years old




Human malaria likely originated in Africa and co-evolved along with its hosts, mosquitoes and non-human primates. The first evidence of malaria parasites was found in mosquitoes preserved in amber from the Paleocene period that are approximately 30 million years old. Malaria may have been a human pathogen for the entire history of the species as humans may have originally caught Plasmodium falciparum from gorillas.


Coinciding with the start of agriculture (Neolithic revolution) about 10,000 years ago, malaria started having a major impact on human survival as certain blood disorders conferred a selective advantage against malaria infection (balancing selection). The disorders included: sickle-cell disease, thalassaemias, glucose-6-phosphate dehydrogenase deficiency, ovalocytosis, elliptocytosis and loss of the Gerbich antigen (glycophorin C) and the Duffy antigen. The three major types of inherited genetic resistance (sickle-cell disease, thalassaemias, and glucose-6-phosphate dehydrogenase deficiency) were present in the Mediterranean world at the time of the Roman Empire, about 2000 years ago.


References to the unique periodic fevers of malaria are found throughout recorded history. According to legend, the Chinese emperor Huang Di (Yellow Emperor, 2697-2590 BCE) ordered the compilation of a canon of internal medicine. The Chinese Huangdi Neijing (The Inner Canon of the Yellow Emperor) apparently refers to repeated paroxysmal fevers associated with enlarged spleens and a tendency to epidemic occurrence – the earliest written report of malaria. In the Sushruta Samhita, a Sanskrit medical treatise (6th century BCE), the symptoms of malarial fever were described and attributed to the bites of certain insects.


The term ‘miasma’ was coined by Hippocrates of Kos who used it to describe dangerous fumes from the ground that are transported by winds and can cause serious illnesses. The name malaria, derived from ‘mal’aria’ (bad air in Medieval Italian) was probably first used by Leonardo Bruni in a publication of 1476. This idea came from the Ancient Romans who thought that this disease came from the horrible fumes from the swamps. The idea that the disease came from the foul gasses released from soil, water and air persisted throughout the 19th century. Malaria was once common in most of Europe and North America, where it is now for all purposes non-existent. The coastal plains of southern Italy, for example, fell from international prominence (the Crusaders going by sea to the Holy Land took ship at Bari) when malaria expanded its reach in the 16th century.


At roughly the same time, in the coastal marshes of England, mortality from “marsh fever” or “the ague” (from Latin “febris acuta”) was comparable to that in sub-Saharan Africa today. William Shakespeare was born at the start of the especially cold period that climatologists call the “Little Ice Age”, yet he was aware enough of the ravages of the disease to mention it in eight of his plays.


Throughout history the most critical factors in the spread or eradication of disease have been human behavior (shifting population centers, changing farming methods and the like) and living standards. Precise statistics do not exist because many cases occur in rural areas where people do not have access to hospitals or the means to afford health care. As a consequence, the majority of cases are undocumented. Poverty has been and remains a reason for the disease to remain while it has undergone a decline in other locations.


Climate change is likely to affect future trends in malaria transmission, but the severity and geographic distribution of such effects is currently uncertain, though attracting increasing scientific attention.


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Radiotherapy and Short-Term Androgen Deprivation for Localized Prostate Cancer




A study published in the New England Journal of Medicine (2011;365:107-118) was designed to evaluate whether short-term androgen-deprivation therapy (ADT) before and during radiotherapy improves cancer control and overall survival among patients with early, localized prostate adenocarcinoma.


From 1994 through 2001,the study randomly assigned 1,979 eligible patients with stage T1b, T1c, T2a, or T2b prostate adenocarcinoma and a prostate-specific antigen (PSA) level of < 20 ng/mL to radiotherapy alone (992 patients) or radiotherapy with 4 months of total androgen suppression starting 2 months before radiotherapy (radiotherapy plus short-term ADT, 987 patients). The primary end point was overall survival. Secondary end points included disease-specific mortality, distant metastases, biochemical failure (an increasing level of PSA), and the rate of positive findings on repeat prostate biopsy at 2 years. The median follow-up period was 9.1 years.


Results showed the 10-year rate of overall survival was 62% among patients receiving radiotherapy plus short-term ADT (the combined-therapy group), as compared with 57% among patients receiving radiotherapy alone (hazard ratio for death with radiotherapy alone, 1.17; P=0.03). The addition of short-term ADT was associated with a decrease in the 10-year disease-specific mortality from 8% to 4% (hazard ratio for radiotherapy alone, 1.87; P=0.001). Biochemical failure, distant metastases, and the rate of positive findings on repeat prostate biopsy at 2 years were significantly improved with radiotherapy plus short-term ADT. Acute and late radiation-induced toxic effects were similar in the two groups. The incidence of grade 3 or higher hormone-related toxic effects was less than 5%. Reanalysis according to risk showed reductions in overall and disease-specific mortality primarily among intermediate-risk patients, with no significant reductions among low-risk patients.


According to the authors, among patients with stage T1b, T1c, T2a, or T2b prostate adenocarcinoma and a PSA level of 20 ng/mL or less, the use of short-term ADT for 4 months before and during radiotherapy was associated with significantly decreased disease-specific mortality and increased overall survival. According to post hoc risk analysis, the benefit was mainly seen in intermediate-risk, but not low-risk, men.

Interleukin-1beta Gene Expression in Peripheral Blood Leukocytes Predicts Risk For Progression of Symptomatic Knee Osteoarthritis




According to an article published in Arthritis & Rheumatism (2011; 63:1908-1917) a study was performed to evaluate whether gene expression profiles could serve as biomarkers of symptomatic knee osteoarthritis (OA). The study examined gene expression profiles in peripheral blood leukocytes (PBLs) from patients with OA and compared them with those from non-OA controls to determine whether candidate genomic biomarkers (PBL expression of inflammatory genes) could predict an increased risk of disease progression in patients with symptomatic radiographic knee OA.


The study evaluated 3 independent cohorts of patients with knee OA and 1 cohort of non-OA control subjects. Two cohorts (a learning cohort and a validation cohort) were recruited at New York University Hospital for Joint Diseases (NYUHJD), and 1 cohort (a validation cohort) was recruited at Duke University Medical Center. PBL gene expression was assessed using Affymetrix microarray and was confirmed by quantitative polymerase chain reaction (qPCR). Radiographic progression at 2 years was assessed in 86 patients.


The study identified 173 genes that were significantly up-regulated or down-regulated (> 1.5-fold change) in OA PBLs, at a false discovery rate of 5%. Cluster analysis revealed 2 distinct subgroups among the patients with OA: those in whom the expression of interleukin-1beta (IL-1beta) was increased > 2-fold compared with controls, and those in whom the expression of IL-1beta was comparable with that in controls. Overexpression of IL-1beta in these OA subclasses was validated using qPCR in all 3 cohorts. Patients with the inflammatory “IL-1beta signature“ had higher pain scores and decreased function and were at higher risk of radiographic progression of OA.


According to the authors, PBLs from patients with symptomatic knee OA display a characteristic transcriptome profile, and that increased expression of IL-1beta identifies a subset of patients with OA who have increased pain and are at higher risk of radiographic progression of OA.

The Effect of Handwashing with Water Alone and With Soap on Child Diarrhea in Rural Bangladesh



Standard public health interventions to improve hygiene in communities with high levels of child mortality, encourage community residents to wash their hands with soap at five separate key events during the day, a recommendation that would require mothers living in impoverished households to typically wash hands with soap more than ten times per day. As a result, a large prospective study, published in PLoS Medicine (2011; 8: e1001052), was performed to assess the relationship between observed handwashing behavior and subsequent childhood diarrhea.


For the study, fieldworkers conducted a 5-hour structured observation and a cross-sectional survey in 347 households from 50 villages across rural Bangladesh in 2007. For the subsequent 2 years, a trained community resident visited each of the enrolled households every month and collected information on the occurrence of diarrhea in the preceding 48 hours among household residents under the age of 5 years.


Results showed that compared with children living in households where persons prepared food without washing their hands, children living in households where the food preparer washed at least one hand with water only (odds ratio [OR] = 0.78), washed both hands with water only (OR = 0.67), or washed at least one hand with soap (OR = 0.30) had less diarrhea.


According to the authors, the study suggests that handwashing before preparing food is a particularly important opportunity to prevent childhood diarrhea, and that handwashing with water alone can also significantly reduce childhood diarrhea.

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FDA Seeks Comments on Proposed Policy for Diagnostic Tests Used with Targeted Drug Therapies



The FDA has issued a new draft guidance to facilitate the development and review of companion diagnostics. Companion diagnostics are tests used to help health care professionals determine whether a patient with a particular disease or condition should receive a particular drug therapy or how much of the drug to give. The draft document is intended to provide companies with guidance on the agency’s policy for reviewing a companion diagnostic and the corresponding therapy. See: FDA Basics Video: Alberto Gutierrez Interviewed on Diagnostic Tests and Personalized Medicine (video).


One common type of companion diagnostic looks for whether a patient has a specific gene amplification or protein over-expression that could predict whether a drug might benefit the patient or lead to harm. For example, the FDA in 1998 approved Herceptin (trastuzumab), a breast cancer drug designed to target HER2 gene amplification or HER2 protein over-expression. The drug was approved with a companion test and today testing is routinely performed on women diagnosed with breast cancer to help health care professionals determine whether or not the patient should receive Herceptin.


The draft guidance:


  1. Clarifies the FDA’s definition of a companion diagnostic;
  2. Recommends early engagement between the FDA and manufacturers so that the agency’s expectations are included in development plans;
  3.  Highlights the FDA’s intention to conduct simultaneous reviews of a drug or biologic therapy and its corresponding companion diagnostic; and
  4. Identifies instances where the FDA may approve a targeted medicine in the absence of a cleared or approved companion diagnostic. In cases where the therapy is intended to treat a serious or life-threatening disease or condition for which there is no available or satisfactory treatment and when the potential benefits outweigh the risks of not having a cleared or approved companion diagnostic, the therapy could be approved first while the companion diagnostic may be approved or cleared later through the appropriate device submission process.


The FDA is seeking public input on the draft guidance for 60 days. Comments can be submitted online or in writing to: Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD  20852.


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 ( 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.

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