Science Weekly podcast: Monitoring climate change in the Antarctic

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We dial up researchers looking at climate change in Antarctica; plus, Clay Shirky explains his answer to this year’s Edge Question

Publication on the Value of EDC Accepted by the DIA Journal

Target Health is pleased to announce that a publication entitled “Evaluation of Data Entry Errors and Data Changes to an Electronic Data Capture (EDC) Clinical Trial Database,” has been accepted for publication by the DIA Journal.  Here is abstract of the abstract:

“The aim of the study 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 the aim, 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.  The main errors observed were simple transcription errors from the paper source documents to the EDC database.  This observation was to be expected, since every transaction has an inherent error rate.  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.”

We are very pleased that contributing authors include Silvana Cappi (Ferring Pharmaceuticals), Ralph D’Agostino, Jr. (Wake Forest University School of Medicine), Yong Joong Kim, Joonhyuk Choi, Glen Park and Jules Mitchel (Target Health) and 2 summer interns who worked on the data (David Horn and Morgan Kist).

This paper is a natural followup to a recent publication in the DIA Journal entitled: Risk-Based Source Data Verification Approaches: Pros and Cons – DIA Journal, November 2010, who lead author was Vadim Tantsyura of Infinity Pharmaceuticals. For a full list of Target Health publications, please visit our website.

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. Target Health’s software tools are designed to partner with both CROs and Sponsors. Please visit the Target Health Website.

Universities Could Identify Depressed Students

One out of every four or five students who visits a university health center for a routine cold or sore throat turns out to be depressed, but most centers miss the opportunity to identify these students because they don’t screen for 1) ___, according to new Northwestern Medicine research.

About 2 to 3% of these depressed students have had 2) ___ thoughts or are considering suicide, the study found.

“Depression 3) ___ is easy to do, we know it works, and it can save lives,” said Michael Fleming, professor of family and community medicine at Northwestern University Feinberg School of Medicine. “It should be done for every student who walks into a health center.”

The consequences of not finding and treating these students can be can be serious and even deadly. “These kids might drop out of school because they are so 4) ___ or hurt or kill themselves by drinking too much or taking drugs,” Fleming said.

“Things continually happen to students – a low grade or problems with a boyfriend or girlfriend – that can 5) ___ depression,” Fleming said. “If you don’t take the opportunity to screen at every visit, you are going to miss these kids.”

The study is the first to screen for depression in a large 6) ___ of students who are coming to campus health centers for routine care. Prior depression studies have been conducted by surveying general college samples or students in counseling centers. The frequency of depression and suicidal thoughts among campus health clinic users was nearly twice as high as rates reported in general college samples.

Depressed students need 7) ___, which may include counseling and medication. These students are more likely to drink, smoke and be involved in intimate partner violence, the study found. With new technology, screening students is simple, Fleming noted. While waiting for an appointment at the health center, the student could answer seven simple 8) ___ – a depression screening tool that that could be immediately entered into his electronic health record. When the doctor or nurse sees the student, she then could address the student’s sadness or depression.

Universities typically separate 9) ___ health treatment from primary care treatment. If a student comes to a campus health center and complains about depression, he is referred to a counseling center. Historical perceptions and biases against preventive screenings are that kids who need treatment the most don’t go to campus health centers, and they won’t tell the truth about their depression. That’s wrong. “Students will tell you the 10) ___,” Fleming said. “If they are sad and depressed, they will tell you that. And, kids who are drinking too much or who are suicidal do go to the campus health centers.”

The study also found that students who exercise frequently are not as depressed. That’s the one thing that seemed to be 11) ___. The study surveyed 1,622 college students at college campuses including the University of Wisconsin, the University of Washington and the University of British Columbia (ref: American Journal of Orthopsychiatry, 2011;81:101)

ANSWERS: 1) depression; 2) suicidal; 3) screening; 4) sad; 5) trigger; 6) population; 7) treatment; 8) questions; 9) mental; 10) truth; 11) protective


The search for potential genetic and environmental causes of schizophrenia began not long after Eugen Bleuler coined the name of the disease in 1908. In the first decades of the 20th century, twin and adoption studies began to consistently point to an inherited component in the susceptibility to the disease. In the decades before the molecular era, the twin data implied that it was a multigenic disease, with multiple genes of modest or small effect. That general sense of a multifactorial etiology became apparent at a time during which evidence for an environmental component came with surprising difficulty. That evidence emerged slowly from careful epidemiologic studies of second-trimester influenza infections, and from the consequences of deliberate starvation of the Dutch population by the Nazis during the winter of 1944. After both events, women who endured these conditions during their second trimesters had more babies who grew up to have schizophrenia. Researchers have also observed that obstetric and perinatal problems are associated with the disease, and they now generally accept that physical problems during pregnancy can increase the likelihood of schizophrenia.

As the molecular era began in the middle of the 20th century, researchers confirmed the likely multigenic nature of schizophrenia’s etiology. Reseachers began applying the first human molecular genetic maps to schizophrenia soon after such maps became available in the 1980s. They have since linked certain chromosomal regions more or less consistently to schizophrenia in different studies, and some genes in those regions appear to be associated with susceptibility.

One recent report indicates a specific gene-environment interaction in schizophrenia, in which traumatic brain injury was more likely to be associated with schizophrenia in patients with a family history of that disorder. In the past the interpersonal environment of the family was thought to play a role in susceptibility, but this does not appear to be the case. Nonetheless, some differences in expressed emotion within families are associated with differences in severity of illness in the patients. The second half of the 20th century also saw the development of biochemical hypotheses for schizophrenia. The most prominent was the dopamine hypothesis that Carlsson and Lindqvist originally put forth in 1963; it was based on the biochemical effects of treatment with the first antipsychotic drugs, which had been introduced only in 1952. Animal studies lent support to what became a building block of antipsychotic drug discovery – the search for dopamine receptor blockers – and treatment, and Carlsson shared a Nobel Prize for this and other research in 2002. At this time multiple classes of dopamine receptors are known. Genetic mutations in dopamine receptors have also been discovered and have been applied to comparisons of patients and controls for decades. At first there appeared to be no association between these genetic changes and susceptibility to schizophrenia, but as evidence accumulated from studies of thousands of normal controls and patients with schizophrenia, a pattern emerged.

Examination and reanalysis of meta-analyses has implicated three dopamine receptors that have genetic variants consistently associated with schizophrenia: DRD1, DRD2, and DRD4 (dopamine receptors 1, 2, and 4). Other evidence also implicates DRD3. The overall picture for schizophrenia is now quite promising. The genes associated with schizophrenia vulnerability are also related to treatment in the case of dopamine receptors. This suggests that treatments might be tailored to the susceptibility variants, and that the tailored treatments would be more effective in patients who had the specific variants. It also suggests that new treatment approaches might be developed from translational research based on the more recently developed gene-disease associations. Finally, it invites research on prevention based on precautionary care of women through deterrence of viral infections during pregnancy, and improvements in obstetric delivery. Source: Elliot S. Gershon is Foundations Fund Professor of Psychiatry and Human Genetics at the University of Chicago.

Herpes Zoster Vaccine in Older Adults and the Risk of Subsequent Herpes Zoster Disease

Approximately 1 million episodes of herpes zoster occur annually in the United States. Although pre-licensure data provided evidence that herpes zoster vaccine works in a select study population under idealized circumstances, the vaccine needs to be evaluated in field conditions.

As a result, a study published in the Journal of the American Medical Association (2011;305:160-166) was performed to evaluate risk of herpes zoster after receipt of herpes zoster vaccine among individuals in general practice settings.

The investigation was a retrospective cohort study from January 1, 2007, through December 31, 2009, of individuals enrolled in the Kaiser Permanente Southern California health plan. Participants were immunocompetent community-dwelling adults aged 60 years or older. The 75,761 members in the vaccinated cohort were age matched (1:3) to 227,283 unvaccinated members.

The main outcome measure was the incidence of herpes zoster.

Results showed that herpes zoster vaccine recipients were more likely to be white, women, with more outpatient visits, and fewer chronic diseases. The number of herpes zoster cases among vaccinated individuals was 6.4 per 1000 person-years, and for unvaccinated individuals it was 13.0 per 1000 person-years. In adjusted analysis, vaccination was associated with a reduced risk of herpes zoster (hazard ratio [HR], 0.45); this reduction occurred in all age strata and among individuals with chronic diseases. Risk of herpes zoster differed by vaccination status to a greater magnitude than the risk of unrelated acute medical conditions, suggesting results for herpes zoster were not due to bias. Ophthalmic herpes zoster (HR, 0.37) and hospitalizations coded as herpes zoster (HR, 0.35) were less likely among vaccine recipients.

According to the authors, among immunocompetent community-dwelling adults aged 60 years or older, receipt of the herpes zoster vaccine was associated with a lower incidence of herpes zoster. The risk was reduced among all age strata and among individuals with chronic diseases.

Efficacy and Safety of Scorpion Antivenom Plus Prazosin Compared With Prazosin Alone For Venomous Scorpion (Mesobuthus Tamulus) Sting

Envenomation, the process by which venom is injected into some animal by the bite (or sting) of a venomous animal, by Mesobuthus tamulus scorpion sting can result in serious cardiovascular effects. Scorpion antivenom is a specific treatment for scorpion sting, while evidence for the benefit of scorpion antivenom and its efficacy compared with that of commonly used vasodilators, such as prazosin, is scarce. As a result, a study published in the British Medical Journal (2011;342:c7136), was performed to assess the efficacy of prazosin combined with scorpion antivenom, compared with prazosin alone, in individuals with autonomic storm caused by scorpion sting.

The investigation was a prospective, open label randomized controlled trial performed in Maharashtra, India. Study participants included 70 patients with grade 2 scorpion envenomation, older than six months, with no cardiorespiratory or central nervous system abnormalities. Interventions included Scorpion antivenom plus prazosin (n=35) or prazosin alone (n=35) assigned by block randomization. Treatment was not masked and the analysis was by intention to treat.

The primary end point was the proportion of patients achieving resolution of the clinical syndrome (sweating, salivation, cool extremities, priapism, hypertension or hypotension, tachycardia) 10 hours after administration of study drugs. Secondary end points were time required for complete resolution of clinical syndrome, prevention of deterioration to higher grade, doses of prazosin required overall and within 10 hours, and adverse events.

Results showed the mean recovery times in hours for the prazosin plus scorpion antivenom group compared with the prazosin alone groups were: sweating 3 vs. 6.6; salivation 1.9 vs. 3; priapism 4.7 vs. 9.4. 32 patients (91.4%) in the prazosin plus antivenom group showed complete resolution of the clinical syndrome within 10 hours of administration of treatment compared with eight patients in the prazosin group (22.9%). Patients from the antivenom plus prazosin group recovered earlier (mean 8 hours) than those in the control group (17.7 hours. The number of patients whose condition deteriorated to a higher grade was similar in both groups (antivenom plus prazosin four of 35, prazosin alone five of 35). Hypotension was reported in fewer patients in the antivenom plus prazosin group (34.3%) than in the prazosin group (19 of 35), but the difference was not statistically significant. No difference was noted in change in blood pressure and pulse rate over time between two groups.

According to the authors, recovery from scorpion sting is hastened by simultaneous administration of scorpion antivenom plus prazosin compared with prazosin alone.

Smoking and Response to Treatment in RA

According to an article published in Arthritis & Rheumatism (2011;63:26-36), a study was performed to determine whether cigarette smoking influences the response to treatment in patients with early rheumatoid arthritis (RA).

For the analysis, the authors retrieved clinical information from 1,998 patients entering the Epidemiological Investigation of Rheumatoid Arthritis (EIRA) early RA cohort from 1996 to 2006, who were also in the Swedish Rheumatology Register (until 2007). Overall, 1,430 of the 1,621 registered patients were followed up from the time of inclusion in the EIRA cohort. Of these, 873 started methotrexate (MTX) monotherapy at inclusion, and 535 later started treatment with a tumor necrosis factor (TNF) inhibitor as the first biologic agent. The primary outcome was a good response according to the European League Against Rheumatism criteria at the 3-month visit. The influence of cigarette smoking (current or past) on the response to therapy was evaluated by logistic regression, with never smokers as the referent group.

Results showed that compared with never smokers, current smokers were less likely to achieve a good response at 3 months following the start of MTX (27% versus 36%; P = 0.05) and at 3 months following the start of TNF inhibitors (29% versus 43%; P = 0.03). In multivariate analyses in which clinical, serologic, and genetic factors were considered, the inverse associations between current smoking and good response remained (adjusted odds ratio [OR] for MTX response 0.60]; adjusted OR for TNF inhibitor response 0.52). The lower likelihood of a good response remained at later followup visits. Evaluating remission or joint counts yielded similar findings. Past smoking did not affect the chance of response to MTX or TNF inhibitors. Evaluating the overall cohort, which reflects all treatments used, current smoking was similarly associated with a lower chance of a good response (adjusted ORs for the 3-month, 6-month, 1-year, and 5-year visits 0.61, 0.65, 0.78, 0.66, and 0.61, respectively).

According to the authors, among patients with early RA who smoke are less likely to respond to treatment with methotrexate and tumor necrosis factor inhibitors.

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

Draft Guidance Addresses Electronic Source Documentation in Clinical Investigations

Congratulations to FDA for addressing direct data entry and guidance on the use of the electronic medical record (EMR) in the clinical trial space. The draft “Guidance for Industry: Electronic Source Documentation in Clinical Investigations” is very well written and provides guidance to sponsors, contract research organizations (CROs), data management centers, and clinical investigators on capturing, using, and archiving electronic data in FDA-regulated clinical investigations.

The guidance is intended to ensure the reliability, quality, integrity, and traceability of electronic source data and source records maintained at the site for FDA inspection, and to promote the capture of source data in electronic form, which will help to:

1. eliminate unnecessary duplication of data

2. reduce the opportunity for transcription errors

3. promote the real-time entry of electronic source data during subject visits

4. ensure the accuracy and completeness of data

(e.g., through the use of electronic prompts for missing or inconsistent data).

This guidance is intended to be used together with the guidances for industry 2 entitled:

1. Computerized Systems Used in Clinical Investigations

2. Part 11, Electronic Records; Electronic Signatures – Scope and Application

3. General Principles of Software Validation; Final Guidance for Industry and FDA Staff

Target Health has provided formal comments to FDA in response to the draft guidance. While Target e*CRF®, in general, complies with the current draft guidance, Target Health has proposed to FDA to restructure the document to reflect current best practices, so that the overall structure of the document addresses 2 tiers 1) Data Entry and Data Cleaning and 2) Data Analysis and Data Archiving), rather than proposed 3 tiers of data flow. The statement that “once investigators have reviewed and signed off on completed portions of the eCRF for a study subject, the data can be archived and transmitted to the parties in Tier 3,” should be revised.

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.