DIA Journal Publication: Evaluation of Data Entry Errors and Data Changes to an Electronic Data Capture (EDC) Clinical Trial Database

Target Health is pleased to announce the publication of an article in the July 2011 edition of the Drug Information Journal (2011;45:421-430): entitled Evaluation of Data Entry Errors and Data Changes to an Electronic Data Capture (EDC) Clinical Trial Database. The article was authored by colleagues from Target Health Inc., Ferring Pharmaceuticals (Silvana Cappi) and Wake Forest University School of Medicine Ralph D’Agostino, Jr.

The aim of the publication was to identify database changes and data entry errors to an Electronic Data Capture (EDC) Clinical Trial Database, and to assess the impact of the changes. To accomplish this, Target e*CRF® was used as the EDC tool for a multinational, dose-finding, multi-center, double-blind, randomized, parallel, placebo-controlled trial to investigate efficacy and safety of a new treatment in men with lower urinary tract symptoms associated with benign prostatic hyperplasia.

There were a total of 2,584 (6.2%) changes to 41,568 eCRF pages which were entered into the EDC database. Of the 2,584 changes, 1,836 (71.1%) were designated due to Data [transcription] Entry Errors, 486 (18.8%) due to Additional Information and 262 (10.1%) due to Other Reasons. It was also demonstrated that of the 2,584 form changes, 2,192 (85%) occurred in 10 forms, 72% occurred in six forms and remarkably, 47% in just three forms.

In order to assess the impact on data interpretation due to changes to the database, an analysis was made of the means and standard deviations (SD), pre and post data cleaning, of five variables. When examining the data from the impact of data changes, it was demonstrated that the mean values of each of the five measurements were nearly identical for the initial and final values. Therefore, in this illustration, the clinical impact on estimating the overall level of the outcome is minimal. In addition, in all cases, the estimate of the SD was smaller in the final cleaned data than in the initial data entry. This points to the area where sponsors of clinical research may need to consider most when determining the impact that errors may have on results when there is a reduced level of SDV in clinical trials where data are transcribed from paper source documents to EDC systems. However, these error rates should be lower when data are entered directly into EDC systems, using direct data entry, since there will be no transaction errors and a reconciliation of all out of range values will occur at the time of data entry.

What and how to monitor must be assessed within the risk-based monitoring section of the Comprehensive Data Monitoring Plan (CDMoP). With the advent of direct data entry, and the elimination of the requirement to transcribe from a paper source record to an EDC system, error rates should go down dramatically. In addition, protocol violations and data outside the normal range can be identified at the time of data entry and not days and weeks and months after the fact.

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.

Drug Can Reverse Overgrown Hearts to Help Prevent Heart Failure

 

 

A promising cancer treatment drug can restore function of a heart en route to failure from high blood pressure, researchers at UT Southwestern Medical Center have found.

A promising cancer treatment drug can restore function of a heart en route to failure from high blood 1) ___, researchers at UT Southwestern Medical Center have found. The drug, a type of HDAC 2) ___ deacetylase inhibitor being evaluated in numerous ongoing clinical trials, has been shown to reverse the harmful effects of autophagy in heart muscle cells of mice. Autophagy is a natural process by which 3) ___ eat their own proteins to provide needed resources in times of stress. The new study appears in Proceedings of the National Academy of Sciences.

This opens the way for a new therapeutic strategy in hypertensive 4) ___ disease, one we can test for potential to promote regression of heart disease, said Dr. Joseph Hill, chief of cardiology and director of the Harry S. Moss Heart Center at UT Southwestern. Dr. Hill, senior author of the study, and other researchers have shown previously that all forms of heart disease involve either too much or too little autophagy, normally an adaptive process. For example, in the presence of high blood pressure, the heart 5) ___, or hypertrophies, and autophagy is turned on. Ultimately, the hypertension-stressed heart can go into failure.

Prior research from Dr. Hill’s laboratory has shown that HDAC inhibitors blunt disease-associated heart 6) ___, so researchers designed this study to determine what impact a particular type of HDAC inhibitor had on autophagy. The researchers engineered mice with overactive autophagy and induced hypertrophy leading to heart 7) ___. Scientists then gave the mice an HDAC inhibitor known to limit autophagy. The heart decreased back to near its normal size, and heart function that had previously been declining went back to normal, Dr. Hill said. That is a powerful observation where disease regression, not just disease 8) ___, was seen.

Dr. Hill noted that the research that led to this finding started decades ago and included studies led by Dr. Kern Wildenthal, former president of UT Southwestern and now president of Southwestern Medical Foundation. This is one of those exciting, but rare, examples where an important finding made originally in yeast moved into mouse models and is soon moving to humans, Dr. Hill said. That’s the Holy Grail for a physician-scientist – to translate those sorts of fundamental molecular discoveries through preclinical studies and ultimately in 9) ___.

ANSWERS: 1) pressure; 2) histone; 3) cells; 4) heart; 5) enlarges; 6) growth; 7) failure; 8) prevention; 9) humans

100 Years later, Homeopath Innocent According to DNA Tests

 

Nearly 100 Years After Being Hung, Homeopath Appears to be Innocent According to Recent DNA Tests

CSI proves Dr Crippen was innocent: DNA tests reveal that remains in their cellar were not his wife.  Modern CSI methods have been used to prove Dr Hawley Crippen – who gained a reputation as one of the most notorious murderers in British history – did not kill his wife. The breakthrough comes more than 100 years after he was hanged for allegedly poisoning his wife, Cora. Now scientists say DNA tests show the remains found at the couple’s home were not hers.

 

 

 

Dr Hawley Crippen and his lover Ethel Le Neve. The pair fled when Dr. Crippen’s wife Cora (far right), was reported missing

The quiet Dr. Crippen moved to the U.K., and worked as a homeopathic doctor in London. His flamboyant and flirtatious wife Cora – also known by her stage name Belle Elmore – was a struggling music hall singer. In January of 1910, Cora disappeared under mysterious circumstances following a dinner party at the couple’s home. Crippen told Cora’s friends that she had returned to the United States to visit relatives, and then soon after, that she had taken ill and died. He then invited scandal by asking his secretary and lover, Ethel Le Neve, to move in with him. Friends grew suspicious, and asked the police to investigate. Crippen told them that Cora had left him for another man, and that he had lied to her friends to save face. When the inspectors returned a few days later to ask more questions, they found that Crippen and Ethel had fled. A thorough search of the Crippen home resulted in the grisly discovery of body parts beneath the cellar. According to the police report, the victim had been poisoned, and then filleted. The horrific murder, so reminiscent of Jack the Ripper’s attacks only two decades earlier, quickly became headline news.

The media glare and close government scrutiny put Scotland Yard under intense pressure to catch Crippen and solve the crime. Even a young Winston Churchill, then Britain’s Home Secretary, was intimately tracking the investigation. Crippen and Le Neve tried fleeing to Canada, but were apprehended after the captain of their ship used a brand new technology, – the Marconi wireless machine – to alert authorities of his whereabouts.

The high-profile case that followed included incriminating pajamas, a rare poison that Crippen was known to have possessed, and a showy pathologist with a red carnation who convinced the jury that marks on the skin samples proved they were from Cora.  A piece of flesh featured a scar similar to one Mrs Crippen had on her torso and a jury took less than half an hour to sentence the homeopath to death.

Trestrail, a poison expert, was troubled by its circumstantial evidence. He had never heard of a poisoning case where the perpetrator had dismembered his victim – poisoners usually did all they could to make death look like an accident. And even if Crippen had committed both acts, why would he have disposed of so much of the body, then left just a few incriminating pieces behind? His questions led to a careful analysis of the court records, and new forensic testing on the physical evidence that still remains from the crime scene. Trestrail traveled between the U.S. and England to piece together details of the infamous crime, working closely with DNA expert Foran and genealogist Wills each step of the way.

Dr. Foran’s team, working in his forensic biology lab at Michigan State University, compared the DNA from the 100-year-old tissue to modern DNA from relatives of Cora that Wills managed to track down. Expecting to confirm that the body was Cora’s, the team instead found that the DNA did not match, and even more startlingly, that the body parts were not even female – they were from a male victim.

With convincing evidence that the body did not belong to Cora, Trestrail began to dig deeper into the police and court archives, slowly unraveling a series of suppressed documents. Among the noted evidence was a letter to Crippen from Cora, in which she claims she is living in America and has no plans to save him from execution. The letter was deemed a hoax by investigators, but was never even shown to Crippen or his lawyers. Could the police have tampered with the evidence used in trial?

Before he was executed, Crippen wrote an eerily prophetic letter to Ethel Le Neve. In it, he said, Face to face with God, I believe that facts will be forthcoming to prove my innocence. Modern forensic science has now fulfilled his prophecy. But now scientists at the University of Michigan claim the remains were actually male. Tests – similar to those used on the Channel 5 drama CSI – compared DNA from the remains to samples from Mrs Crippen’s living relatives and found no match. Lead scientist David Foran said: Based on genealogical and DNA research, the tissue used to convict Dr Crippen was not that of his wife Cora and further DNA testing showed the tissue was male.

The findings were published in the Journal of Forensic Science in America and were co-authored by poisoning expert John Trestrail.

 

 

1910 – Dr Crippen with Ms Le Neve during their trial for murder.  The homeopath

was found guilty and executed, while his alleged accomplice was acquitted

Watch the PBS video

The Environment and Autism

According to results from the California Autism Twins Study (CATS), published in the July 2011 issue of the Archives of General Psychiatry, it was found that environments, such as those shared by fraternal twins, influences susceptibility to autism more than previously thought. The study, supported by the National Institutes of Health, found that shared environmental factors – experiences and exposures common to both twin individuals – accounted for 55% of strict autism and 58% of more broadly defined autism spectrum disorders (ASD), and that genetic heritability accounted for 37% of autism and 38% of ASD. Random environmental factors not shared among twins played a much smaller role.

Earlier twin studies had estimated the genetic heritability of autism to be as high as 90%, due to much lower estimates of concordance – both members of a twin pair having the disorder – in fraternal twins. The new study found such concordance to be four to five times higher.

The study is the first to analyze a large sample of twins drawn from the general population. Previous twin studies have been based on more limited samples, such as patients in treatment. It is also the first to employ the latest standard in diagnosing autism, which requires structured clinical assessments based on interviews with the parents as well as direct observation of the child.

Drawing upon state records, the study initially identified 1,156 twin pairs, with at least one member affected by an ASD, born to California mothers between 1987 and 2004. The children were all at least 4 years old, an age when autism can be reliably diagnosed. Ultimately, this group was winnowed for genetic analysis to 192 twin pairs – 54 identical and 138 fraternal. Since autism disproportionately affects males, males outnumbered females by four to five times, with 80 of the pairs including both genders.

Results showed that concordance for ASD was 77% among identical male pairs, and 31% among fraternal male pairs. In females, concordance for ASD was more closely spaced – 50% for identical and 36% for fraternal pairs. By contrast, previous studies had found concordance rates for fraternal twins that were much lower, ranging only in the single digits.

According to the authors, increasingly, evidence is accumulating that overt symptoms of autism emerge around the end of the first year of life. Because the prenatal environment and early postnatal environment are shared between twin individuals, the author hypothesize that at least some of the environmental factors impacting susceptibility to autism exert their effect during this critical period of life. Nongenetic risk factors that may index environmental influences include parental age, low birth weight, multiple births, and maternal infections during pregnancy. The authors add that future studies that seek to elucidate such factors and their role in enhancing or suppressing genetic susceptibility are likely to enhance our understanding of autism.

Adherence to a Low-Risk, Healthy Lifestyle and Risk of Sudden Cardiac Death Among Women

Sudden cardiac death (SCD) accounts for more than half of all cardiac deaths. The majority of SCD events occur as the first manifestation of heart disease, especially among women. Primary preventive strategies are needed to reduce SCD incidence. As a result, a study published in the Journal of the American Medical Association (2011;306:62-69) was performed to estimate the degree to which adherence to a healthy lifestyle may lower the risk of SCD among women.

The investigation was a prospective cohort study of 81,722 US women who participated in the Nurses’ Health Study from June 1984 to June 2010. Lifestyle factors were assessed via questionnaires every 2 to 4 years. A low-risk lifestyle was defined as not smoking, body mass index of less than 25, exercise duration of 30 minutes/day or longer, and top 40% of the alternate Mediterranean diet score, which emphasizes high intake of vegetables, fruits, nuts, legumes, whole grains, and fish and moderate intake of alcohol.

The main outcome measure was sudden cardiac death (defined as death occurring within 1 hour after symptom onset without evidence of circulatory collapse).

During the observation period, there were 321 cases of SCD during 26 years of follow-up with a mean age of 72 years at the time of the SCD event. All 4 low-risk lifestyle factors were significantly and independently associated with a lower risk of SCD. The absolute risks of SCD were 22 cases/100,000 person-years among women with 0 low-risk factors, 17 cases/100,000 person-years with 1 low-risk factor, 18 cases/100,000 person-years with 2 low-risk factors, 13 cases/100,000 person-years with 3 low-risk factors, and 16 cases/100,000 person-years with 4 low-risk factors.

Compared with women with 0 low-risk factors, the multivariable relative risk of SCD was 0.54 for women with 1 low-risk factor, 0.41 for 2 low-risk factors, 0.33 for 3 low-risk factors, and 0.08 for 4 low-risk factors. The proportion of SCD attributable to smoking, inactivity, overweight, and poor diet was 81%. Among women without clinically diagnosed coronary heart disease, the percentage of population attributable risk was 79%.

According to the authors, adherence to a low-risk lifestyle is associated with a low risk of SCD.

Inactivity and Risk of Idiopathic Pulmonary Embolism Among Women

According to a study published in the British Medical Journal (2011;343:d3867), a prospective cohort study was performed to determine the association between physical inactivity (that is, a sedentary lifestyle) and incident idiopathic pulmonary embolism. Study participants included 69,950 female nurses who completed biennial questionnaires from 1990 to 2008.

The primary outcome was idiopathic pulmonary embolism confirmed in medical records. The statistical analysis controlled for age, body mass index (BMI), energy intake, smoking, pack years, race, spouse’s educational attainment, parity, menopause, non-aspirin non-steroidal anti-inflammatory drugs, warfarin, multivitamin supplements, hypertension, coronary heart disease, rheumatological disease, and dietary patterns. The primary exposure was physical inactivity, measured in hours of sitting each day. The secondary exposure was physical activity, measured in metabolic equivalents a day.

Over the 18 year study period, there were 268 cases of incident idiopathic pulmonary embolism. Results showed an association between time of sitting and risk of idiopathic pulmonary embolism (41/104,720 vs. 16/14,565 in most inactive (P<0.001 for trend). The risk of pulmonary embolism was more than twofold in women who spent the most time sitting compared with those who spent the least amount of time sitting (hazard ratio 2.34). There was no association between physical activity and pulmonary embolism (P=0.53 for trend).

According to the authors, physical inactivity is associated with incident pulmonary embolism in women and that interventions that decrease time sitting could lower the risk of pulmonary embolism.

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

FDA Proposes New Policy for Some Diagnostic and Radiology Devices

The FDA has issued a draft guidance describing its intent to exercise enforcement discretion with respect to the premarket notification requirements for certain in vitro diagnostic and radiology devices with well-established safety and effectiveness profiles. The draft guidance lists 30 different device types, including common urine and blood tests, alcohol breath tests, blood clotting protein tests, and radiology device accessories, such as film cassettes, film processors, and digitizers. FDA intends to exempt these devices from premarket notification requirements through the appropriate regulatory processes. In the meantime, however, FDA does not intend to enforce the premarket notification requirements with respect to these devices provided that they do not exceed the limitations on exemption specified in the device classification regulations.

FDA intends to continue to enforce all other applicable requirements, including, but not limited to, registration and listing and Good Manufacturing Practices as set forth in the Quality System regulations.

According to FDA, by addressing the risk level of these devices, the agency is taking a smart regulatory approach that eases unnecessary requirements for manufacturers, while making sure the public has safe and effective devices.

The device types listed in the draft guidance include devices identified by the FDA as those for which less stringent oversight would not compromise public health. The FDA is seeking further comment on the draft guidance from manufacturing, clinical and patient communities. The draft guidance is open for comment for 90 days. In the future, the FDA also intends to reduce the pre-market regulatory burden on additional in vitro diagnostic and radiology device types.

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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