Target Health Kicks Off a Phase 3 Program Using eSource
A Picture is Worth a Thousand Words.
This is the original Target Health Inc. photo that’s going viral in the industry
This past week, in the heart of NYC, Target Health managed a Protocol Initiation Meeting (PIM; aka Investigator Meeting) to kick off a 20-center Phase 3 study. What made this meeting different from traditional PIMs, was the extensive training on the paperless tools to be used during the course of the study. By the time the meeting concluded, it was clear that the approach was working. In fact, one site indicated that they preferred to have additional training, which was music to the ears of the sponsor and all present. Clearly, as the industry transitions to the paperless clinical trial and direct data entry at the time of the office visit, there is no room for a lack of understanding of all study procedures and activities. At the beginning and during the meeting, the message was:
1. Subject safety is paramount
2. Focus and follow the protocol
3. Because we are now paperless, we will “bother“ you less with onsite monitoring visits
4. There is now minimal transcription to EDC systems so you are no longer data entry clerks
5. You will now be able to focus more on patient care and protocol compliance
6. We will monitor the data every day and you will hear from us
7. We will monitor the metadata and compare quality metrics among the sites
8. We are always available for calls when you have questions on any issue
9. There can be no protocol exceptions
10. This will be a transformational study
The software tools to be used in the study are:
1. Target e*CRF® (EDC)
2. Target Document® (eTMF)
3. Target e*CTR® (eClinical Trial Record; eSource).
The eClinical Trial Record (Target e*CTR) is equivalent to electronic health record for clinical trials in that the clinical trial data are entered directly into an electronic data capture system in real time, at the time of the office visit.
4. Target e*Pharmacovigilance (SAE management)
Psychiatry Manual Drafters Back Down on Diagnoses
Last week, the New York Times reported that, in a rare step, doctors on a panel revising psychiatry’s influential diagnostic manual have backed away from two controversial proposals that would have expanded the number of people identified as having psychotic or depressive 1) ___. The doctors dropped two diagnoses that they ultimately concluded were not supported by the evidence: “attenuated psychosis syndrome,” proposed to identify people at risk of developing 2) ___, and “mixed anxiety depressive disorder,” a hybrid of the two mood problems. They also tweaked their proposed definition of depression to allay fears that the normal 3) ___ people experience after the loss of a loved one, a job or a marriage would be mistaken for a mental disorder.
But the panel, appointed by the American Psychiatric Association to complete the fifth edition of its 4) ___ and ___ ___ of Mental Disorders, or D.S.M., did not retreat from another widely criticized proposal, to streamline the definition of autism. Predictions by some experts that the new definition will sharply reduce the number of people given a diagnosis are off base, panel members said, citing evidence from a newly completed study.
Both the study and the newly announced reversals are being debated this week at the psychiatric association’s annual meeting in Philadelphia, where dozens of sessions were devoted to the D.S.M., the standard reference for 5) ___ disorders, which drives research, treatment and insurance decisions. Dr. David J. Kupfer, a professor of psychiatry at the University of Pittsburgh and the chairman of the task force making revisions, said the changes came in response mainly to field trials – real-world studies testing whether newly proposed diagnoses are reliable from one psychiatrist to the next – and also public commentary. “Our intent for disorders that require more evidence is that they be studied further, and that people work with the criteria” and refine them, Dr. Kupfer said.
The psychiatric association has posted its proposals online, inviting public reaction. More than 10,500 comments have come through the site, many of them critical. “At long last, DSM 5 is correcting itself and has rejected its worst proposals,” said Dr. Allen Frances, a former task force chairman and professor emeritus at Duke University who has been one of the most prominent critics. “But a great deal more certainly needs to be accomplished. Most important are the elimination of other dangerous new 6) ___ and the rewriting of all the many unreliable criteria sets.” The criticism of “mixed anxiety depressive disorder” was that it would unnecessarily tag millions of moderately neurotic people with a 7) ___ label. Mixed states of depression and anxiety can be severe, but the proposed hybrid had looser criteria than either depression or anxiety on its own – lowering the bar significantly for a diagnosis.
The primary concern with “attenuated psychosis syndrome” was that it would lead to unwarranted drug treatment of youngsters. The diagnosis was meant to identify people, usually 8) ___, who exhibit psychosis-like symptoms and treat them early. But 70% to 80% of people who report having weird thoughts and odd hallucinations do not ever qualify for a full-blown diagnosis – and might be treated for something they did not have. On the manual’s site, in blogs and other public forums, advocates, therapists, scientists and people receiving services sounded off on the proposed changes. The psychiatric association made an effort to listen, Dr. Kupfer said. The site “is not just a P.R. effort,” he said. “We’re getting feedback, and it all goes to the working groups.”
The proposed definition of 9) ___, which would eliminate related labels like Asperger’s syndrome and “pervasive developmental disorder,” came under fire in January, when researchers at Yale University presented evidence that about half of the people who currently have a diagnosis on the higher functioning end of the “autism spectrum” would no longer qualify under the new definition. At this week’s annual meeting, researchers presented data from an unpublished study of some 300 children, finding that the proposed definition would exclude very few who currently have a diagnosis of autism or a related disorder. But meeting attendees got mixed messages on autism. In a talk on Tuesday, Dr. Susan E. Swedo, head of the panel proposing the new definition, said that many people who identify themselves as “aspies,” for 10) ___ syndrome, “don’t actually have Asperger’s disorder, much less an autism spectrum disorder.” Dr. Swedo is a researcher at the NIMH.
The issue is hardly settled. Findings from published studies are conflicting, but three recent analyses provide support for the Yale estimate, and more papers in the pipeline are also documenting a significant reduction in numbers of those who would qualify under the new criteria. Getting such a diagnosis is critical to obtain state-financed services for children with special needs. “I certainly hope the D.S.M. task force is right, that the numbers won’t change much,” said Dr. Fred R. Volkmar, director of the Child Study Center at the Yale School of Medicine and senior author of the study presented in January. But if the new definition does not change who gets a diagnosis, he asked, “Why mess with it at all?”
The D.S.M. panel also made an attempt to clarify the difference between normal sadness and 11) ___, by spelling it out in a footnote added to the proposed depression definition. The note reads, in part, “The normal and expected response to an event involving significant loss, including feelings of intense sadness, rumination about the loss, insomnia, poor appetite and weight loss, may resemble a depressive episode” but is not necessarily one. Judging from the past year, the normal and expected response to most of these revisions will be more contentious disagreement that will most likely intensify over the coming weeks. The psychiatric association sent out reminders this week that the current – and final – period for public comment ends on June 15. The final draft of the manual is due at the printer at the end of the year and is scheduled for release in May 2013.
The current edition of the Diagnostic and Statistical Manual of Mental Disorders. The manual affects treatment, research and insurance. Photo Credit: Sam Hodgson for The New York Times
ANSWERS: 1) disorders; 2) psychosis; 3) sadness; 4) Diagnostic and Statistical Manual; 5) mental; 6) diagnoses; 7) psychiatric; 8) young; 9) autism; 10) Asperger’s; 11) depression
The Rosenhan Experiment
St. Elizabeth’s psychiatric hospital, Washington, D.C., one of the sites of the Rosenhan experiment.
The Rosenhan experiment was a famous experiment into the validity of psychiatric diagnosis conducted by psychologist David Rosenhan in 1973. The results were published in the journal Science under the title “On being sane in insane places.” The study is considered an important and influential criticism of psychiatric diagnosis. Rosenhan’s study was done in two parts. The first part involved the use of healthy associates or “pseudopatients” (three women and five men) who briefly simulated auditory hallucinations in an attempt to gain admission to 12 different psychiatric hospitals in five different states. All were admitted and diagnosed with psychiatric disorders. After admission, the pseudopatients acted normally and told staff that they felt fine and had not experienced any more hallucinations. Hospital staff failed to detect a single pseudopatient, and instead believed that all of the pseudopatients exhibited symptoms of ongoing mental illness. Several were confined for months. All were forced to admit to having a mental illness and agree to take antipsychotic drugs as a condition of their release.
The second part involved an offended hospital challenging Rosenhan to send pseudopatients to its facility, whom its staff would then detect. Rosenhan agreed and in the following weeks out of 193 new patients the staff identified 41 as potential pseudopatients, with 19 of these receiving suspicion from at least 1 psychiatrist and 1 other staff member. In fact Rosenhan had sent no-one to the hospital. The study concluded, “It is clear that we cannot distinguish the sane from the insane in psychiatric hospitals” and also illustrated the dangers of dehumanization and labeling in psychiatric institutions. It suggested that the use of community mental health facilities which concentrated on specific problems and behaviors rather than psychiatric labels might be a solution and recommended education to make psychiatric workers more aware of the social psychology of their facilities.
This is the way it happened. Rosenhan himself and seven mentally healthy associates, called “pseudopatients”, attempted to gain admission to psychiatric hospitals by calling for an appointment and feigning auditory hallucinations. The hospital staffs were not informed of the experiment. The pseudopatients included a psychology graduate student in his twenties, three psychologists, a pediatrician, a psychiatrist, a painter and a housewife. None had a history of mental illness. Pseudopatients used pseudonyms, and those who worked in the mental health field were given false jobs in a different sector to avoid invoking any special treatment or scrutiny. Apart from giving false names and employment details, further biographical details were truthfully reported. During their initial psychiatric assessment, they claimed to be hearing voices of the same gender as the patient which were often unclear, but which seemed to pronounce the words “empty”, “hollow”, “thud” and nothing else. These words were chosen as they vaguely suggest some sort of existential crisis and for the lack of any published literature referencing them as psychotic symptoms. No other psychiatric symptoms were claimed. If admitted, the pseudopatients were instructed to “act normally,” reporting that they felt fine and no longer heard voices. Hospital records obtained after the experiment indicate that all pseudopatients were characterized as friendly and cooperative by staff.
All were admitted to 12 different psychiatric hospitals across the United States, including rundown and underfunded public hospitals in rural areas, urban university-run hospitals with excellent reputations, and one expensive private hospital. Though presented with identical symptoms, 7 were diagnosed with schizophrenia at public hospitals, and one with manic-depressive psychosis, a more optimistic diagnosis with better clinical outcomes, at the private hospital. Their stays ranged from 7 to 52 days, and the average was 19 days. All were discharged with a diagnosis of schizophrenia “in remission,” which Rosenhan takes as evidence that mental illness is perceived as an irreversible condition creating a lifelong stigma rather than a curable illness.
Despite constantly and openly taking extensive notes on the behavior of the staff and other patients, none of the pseudopatients were identified as impostors by the hospital staff, although many of the other psychiatric patients seemed to be able to correctly identify them as impostors. In the first three hospitalizations, 35 of the total of 118 patients expressed a suspicion that the pseudopatients were sane, with some suggesting that the patients were researchers or journalists investigating the hospital. Hospital notes indicated that staff interpreted much of the pseudopatients’ behavior in terms of mental illness. For example, one nurse labeled the note-taking of one pseudopatient as “writing behavior” and considered it pathological. The patients’ normal biographies were recast in hospital records along the lines of what was expected of schizophrenics by the then-dominant theories of its etiology.
The pseudopatients were required to get out of the hospital on their own by getting the hospital to release them, though a lawyer was retained to be on call for emergencies when it became clear that the pseudopatients would not ever be voluntarily released on short notice. Once admitted and diagnosed, the pseudopatients were not able to obtain their release until they agreed with the psychiatrists that they were mentally ill and began taking antipsychotic medications, which they flushed down the toilet. No staff member noticed that the pseudopatients were flushing their medication down the toilets and did not report patients doing this.
Rosenhan and the other pseudopatients reported an overwhelming sense of dehumanization, severe invasion of privacy, and boredom while hospitalized. Their possessions were searched randomly, and they were sometimes observed while using the toilet. They reported that though the staff seemed to be well-meaning, they generally objectified and dehumanized the patients, often discussing patients at length in their presence as though they were not there, and avoiding direct interaction with patients except as strictly necessary to perform official duties. Some attendants were prone to verbal and physical abuse of patients when other staff were not present. A group of bored patients waiting outside the cafeteria for lunch early were said by a doctor to his students to be experiencing “oral-acquisitive” psychiatric symptoms. Contact with doctors averaged 6.8 minutes per day.
“I told friends, I told my family, ‘I can get out when I can get out. That’s all. I’ll be there for a couple of days and I’ll get out.’ Nobody knew I’d be there for two months. The only way out was to point out that they’re [the psychiatrists] correct. They had said I was insane, ‘I am insane; but I am getting better.’ That was an affirmation of their view of me.” – David Rosenhan in the BBC program “The Trap.”
For this experiment, Rosenhan used a well-known research and teaching hospital, whose staff had heard of the results of the initial study but claimed that similar errors could not be made at their institution. Rosenhan arranged with them that during a three month period, one or more pseudopatients would attempt to gain admission and the staff would rate every incoming patient as to the likelihood they were an impostor. Out of 193 patients, 41 were considered to be impostors and a further 42 were considered suspect. In reality, Rosenhan had sent no pseudopatients and all patients suspected as impostors by the hospital staff were ordinary patients. This led to a conclusion that “any diagnostic process that lends itself too readily to massive errors of this sort cannot be a very reliable one”. Studies by others found similarly problematic diagnostic results.
Many defended psychiatry, arguing that as psychiatric diagnosis relies largely on the patient’s report of their experiences, faking their presence no more demonstrates problems with psychiatric diagnosis than lying about other medical symptoms. In this vein, psychiatrist Robert Spitzer quoted Kety in a 1975 criticism of Rosenhan’s study: If I were to drink a quart of blood and, concealing what I had done, come to the emergency room of any hospital vomiting blood, the behavior of the staff would be quite predictable. If they labeled and treated me as having a bleeding peptic ulcer, I doubt that I could argue convincingly that medical science does not know how to diagnose that condition. Rosenhan replied that if they continue thinking that you still have an ulcer during x weeks despite having no other symptoms of ulcer, that makes for a big problem. Kety also argued that psychiatrists should not necessarily be expected to assume that a patient is pretending to have mental illness, thus the study lacked realism. Rosenhan called this the “experimenter effect” or “expectation bias,” something indicative of the problems he uncovered rather than a problem in his methodology. The experiment “accelerated the movement to reform mental institutions and to deinstitutionalize as many mental patients as possible.” David L. Rosenhan PhD Born 1929 – recently passed away on February 6, 2012
NIH Launches Collaborative Development Program with Big Pharma to Spur Therapeutic Development
The NIH has unveiled a collaborative program that will match researchers with a selection of pharmaceutical industry compounds to help scientists explore new treatments for patients. NIH’s new National Center for Advancing Translational Sciences (NCATS) has partnered initially with Pfizer, AstraZeneca, and Eli Lilly and Company which have agreed to make dozens of their compounds available for this initiative’s pilot phase.
In recent years, researchers have succeeded in identifying the causes of more than 4,500 diseases. But it has proven difficult to turn such knowledge into new therapies; effective treatments exist for only about 250 of these conditions. NCATS was established last year to help address this gap. It supports rigorous scientific research designed to reengineer elements of the development pipeline to move basic research findings into new treatments for patients.
Some compounds do not prove effective for the specific use for which they were developed; however, if additional research is conducted, they may succeed for a different therapeutic use. A prime example of a compound that did not prove effective for its initial use but succeeded for a different use is azidothymidine (AZT), which failed to show efficacy against cancer, but was later found to be the first medicine effective against HIV, the virus that causes AIDS.
The initiative, Discovering New Therapeutic Uses for Existing Molecules, will direct researchers’ attention to a part of the therapeutic pipeline that traditionally has been difficult for them to access: compounds that already have cleared several key steps in the development process, including safety testing in humans.
The President’s fiscal year 2013 budget proposed $575 million for NCATS, of which approximately $20 million total will be provided to support research grants of up to three years duration for pre-clinical and clinical feasibility studies. These studies will test more than 20 compounds from industry partners for their effectiveness against a variety of diseases and conditions. The companies will provide the researchers with access to the compounds and related data.
The pilot program incorporates innovative template agreements designed to streamline the legal and administrative process for participation by multiple organizations. These template agreements reduce time, cost, and effort, as well as allow greater participation than traditional partnerships. The templates also provide a roadmap for handling intellectual property used in or developed through the program. Participating industry partners will retain the ownership of their compounds, while academic research partners will own any intellectual property they discover through the research project with the right to publish the results of their work.
For more details about this program please see Notices (NOI and RFI) or visit www.ncats.nih.gov/research/reengineering/rescue-repurpose/therapeutic-uses/therapeutic-uses.html.
Global Infant Mortality from 2000 to 2010
Target Health congratulates The Bill & Melinda Gates Foundation for their continuing contribution to the health of the planet.
A study supported by The Bill & Melinda Gates Foundation and published online in the Lancet (11 May 2012), has reported the latest estimates of causes of child mortality in 2010 with time trends since 2000.
For the study, updated total numbers of deaths in children aged 0-27 days and 1-59 months were applied to the corresponding country-specific distribution of deaths by cause. In order to derive the number of deaths in children aged 1-59 months,1) vital registration data was used for countries with an adequate vital registration system; 2) a multinomial logistic regression model was applied to vital registration data for low-mortality countries without adequate vital registration; 3) a similar multinomial logistic regression was used with verbal autopsy data for high-mortality countries; 4) national models were developed for India and China.
Results showed that of 7.6 million deaths in children younger than 5 years in 2010, 64.0% were attributable to infectious causes and 40.3% occurred in neonates. Preterm birth complications (14.1%), intrapartum-related complications (9.4%), and sepsis or meningitis (5.2%) were the leading causes of neonatal death. In older children, pneumonia (14.1%), diarrhea (9.9%), and malaria (7.4%) claimed the most lives. Despite tremendous efforts to identify relevant data, the causes of only 2.7% of deaths in children younger than 5 years were medically certified in 2010.
Between 2000 and 2010, the global burden of deaths in children younger than 5 years decreased by 2 million, of which pneumonia, measles, and diarrhea contributed the most to the overall reduction (0.451 million, 0.363 million and 0.359 million, respectively). However, only tetanus, measles, AIDS, and malaria (in Africa) decreased at an annual rate sufficient to attain the Millennium Development Goal.
According to the authors, child survival strategies should direct resources toward the leading causes of child mortality, with attention focusing on infectious and neonatal causes. More rapid decreases from 2010 to 2015 will need accelerated reduction for the most common causes of death, notably pneumonia and preterm birth complications. The authors added that continued efforts to gather high-quality data and enhance estimation methods are essential for the improvement of future estimates.
Excessive Daytime Sleepiness and Vascular Events: The Three City Study
Excessive daytime sleepiness (EDS) is characterized by persistent sleepiness, and often a general lack of energy, even after apparently adequate night time sleep. EDS is a symptom of sleep disorder hypersomnia. Another symptom is prolonged nighttime sleep. Some persons with EDS, including those with narcolepsy, are compelled to nap repeatedly during the day; fighting off increasingly strong urges to sleep during inappropriate times such as while driving, while at work, during a meal, or in conversations. As the compulsion to sleep intensifies, the ability to complete tasks sharply diminishes, often mimicking the appearance of intoxication.
According to an article published in the Annals of Neurology (2012;71: 661-667),a study was performed to assess whether excessive daytime sleepiness (EDS) at baseline is associated with subsequent coronary heart disease (CHD) and stroke events.
The Three City Study, a French population-based multicenter prospective study, included 7,007 subjects aged >65 years. Study subjects had 1) no personal history of CHD, stroke, or dementia, and 2) self-rated EDS as never, rare, regular, or frequent in response to a face-to-face questionnaire.
The mean age of the cohort was 73.7 years, 63% were women, and 13.3% and 4.3% reported regular and frequent EDS, respectively. After a median follow-up period of 5.1 years, 372 subjects experienced a first event, either stroke (122 subjects) or a CHD event (250 subjects). Interestingly, the increased risk of CHD and stroke was confined to the group with frequent EDS, and was 1.73 as much as in the group that reported never having EDS. This association was seen in those without hypertension but not in those with hypertension at baseline (p for interaction = 0.01). Moreover, the association with frequent EDS was statistically significant for stroke (HR, 2.10) but not for CHD (HR, 1.51).
According to the authors, the current study suggests that frequent EDS is independently associated with future vascular events and stroke in particular in healthy community-dwelling elderly subjects.
TARGET HEALTH excels in Regulatory Affairs. Each week we highlight new information in this challenging area.
FDA Issues Alert on Potential Dangers of Unproven Treatment for Multiple Sclerosis
Chronic cerebrospinal venous insufficiency (CCSVI) uses balloon angioplasty devices or stents to widen narrowed veins in the chest and neck. FDA has learned of death, stroke, detachment and migration of the stents, damage to the treated vein, blood clots, cranial nerve damage and abdominal bleeding associated with this experimental procedure. Balloon angioplasty devices and stents have not been approved by the FDA for use in treating CCSVI.
Multiple sclerosis (MS) is a progressive, immune-mediated disorder of the brain and spinal cord. In MS, the lining around nerve fibers, and often the nerve fibers themselves, in the brain and spinal cord are injured, resulting in significant and disabling neurological symptoms. The underlying cause of MS is not known.
The FDA is now alerting health care professionals and patients about injuries and death associated with the use of an experimental procedure sometimes called “liberation therapy” or the “liberation procedure” to treat CCSVI. Some researchers believe that CCSVI, which is characterized by a narrowing (stenosis) of veins in the neck and chest, may cause MS or may contribute to the progression of the disease by impairing blood drainage from the brain and upper spinal cord. However, studies exploring a link between MS and CCSVI are inconclusive, and the criteria used to diagnose CCSVI have not been adequately established.
Because there is no reliable evidence from controlled clinical trials that this procedure is effective in treating MS, FDA is encouraging rigorously-conducted, properly-targeted research to evaluate the relationship between CCSVI and MS. FDA added that patients are encouraged to discuss the potential risks and benefits of this procedure with a neurologist or other physician who is familiar with MS and CCSVI, including the CCSVI procedures and their outcomes.”
Complications following CCSVI treatment can be reported through MedWatch, the FDA Safety Information and Adverse Event Reporting program.
The FDA also is notifying physicians and clinical investigators who are planning or conducting clinical trials using medical devices to treat CCSVI that they must comply with FDA regulations for investigational devices. Any procedures conducted are considered significant risk clinical studies and require FDA approval, called an investigational device exemption.
In February 2012, the FDA sent a warning letter to a sponsor/investigator who was conducting a clinical study of CCSVI treatment without the necessary approval. The sponsor/investigator voluntarily closed the study.