Target Health Champions eTrial Master File (eTMF)

 

 

Target Document® is now being used for all Target Health clinical trials to manage the eTrial Master File (eTMF). Not only is it being used by both the clinical sites and Target Health CRAs and Project Managers to manage the entire eTMF, several CROs and Sponsors have brought it in-house for their own use.

 

Features include:

 

  1. Web-based
  2. Advanced user management
  3. Electronic signatures to groups and individuals
  4. Document check-in and check-out
  5. Active Bulletin Board
  6. Document expiration notification
  7. Extraordinary ROI
  8. etc

 

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 www.targethealth.com

Sleeplessness Agitates the Brain

 

 

As fatigue grows, electrical activity mounts. Sleep deprivation makes the 1) ___ groggy, but as waking hours mount nerve cells grow increasingly jumpy, a new study shows. This amped-up state may explain why seizures and 2) ___ can accompany an all-nighter. More generally, the results help clarify what goes wrong in a brain deprived of sleep. “It’s an important finding,” says neuroscientist Christopher Colwell of UCLA. “Sleep deprivation is an area of huge interest because most of us do not get enough 3) ___.”

 

By subjecting six people to a night of sleep 4) ___ and measuring their brain responses, Marcello Massimini of the University of Milan and colleagues found that people’s brains become more reactive as hours awake accumulate. To look for signs of altered brain function, the team delivered a jolt of magnetic current to the participants’ skulls that kicked off an electrical response in the 5) ___ cells (an effect like the noise made when a hammer strikes a bell). With electrodes on the scalp, the team measured the strength of this electrical response in the frontal cortex, a brain region that’s involved in making executive 6) ___. After a night of sleep deprivation, participants’ 7) ___ responses were stronger than they were the previous day, the scientists report online February 7 in Cerebral Cortex. This overreaction disappeared after a night’s sleep.

 

The results offer support for a theory of why people sleep: During waking hours, the brain accumulates connections between nerve cells as new things are learned. Sleep, the theory says, sweeps the brain of extraneous clutter, leaving behind only the most important 8) ___. Enhanced excitability in the brain may explain why sleep deprivation can trigger seizures, events marked by massive nerve cell excitation. When doctors want to induce 9) ___ in patients in the clinic, one of the most effective ways is to keep a person awake all night. The new results also have an intriguing link to depression. For some people, sleep deprivation can quickly reverse symptoms of depression, an effect that may be due to the brain’s boosted excitability. The team plans on studying people with 10) ___ to see if their brains show similar responses to sleep deprivation.

 

ANSWERS: 1) brain; 2) hallucinations; 3) sleep; 4) deprivation; 5) nerve; 6) decisions; 7) electrical; 8) connections; 9) seizures; 10) depression

Egyptian Medical Text: The Edwin Smith Papyrus

 

 

The Edwin Smith Papyrus is an Ancient Egyptian medical text on surgical trauma. It dates to Dynasties 16-17 of the Second Intermediate Period in Ancient Egypt, ca. 1600 BCE. The Edwin Smith papyrus is unique among the medical papyri that survive today. While other papyri, such as the Ebers Papyrus and London Medical Papyrus, are medical texts based in magic, the Edwin Smith Papyrus presents a rational and scientific approach to medicine in Ancient Egypt.

 

The Edwin Smith papyrus is 4.68 m in length, divided into 17 pages. The recto, the front side, is 377 lines long, while the verso, the backside, is 92 lines long. Aside from the fragmentary first sheet of the papyrus, the remainder of the papyrus is fairly intact. The papyrus is written in hieratic, the Egyptian cursive form of hieroglyphs, in black and red ink. The vast majority of the papyrus is concerned with trauma and surgery. On the recto side, there are 48 cases of injury. Each case details the type of the injury, examination of the patient, diagnosis and prognosis, and treatment. The verso side consists of eight magic spells and five prescriptions. The spells of the verso side and two incidents in Case 8 and Case 9 are the exceptions to the practical nature of this medical text.

 

Authorship of the Edwin Smith Papyrus is debated. The majority of the papyrus was written by one scribe, with only small sections written by a second scribe. The papyrus ends abruptly in the middle of a line, without any inclusion of an author. It is believed that the papyrus is based upon an earlier text from the Old Kingdom. Form and commentary included in the papyrus give evidence to the existence of an earlier document. The text is attributed by some to Imhotep, an architect, high priest, and physician of the Old Kingdom, 3000-2500 BCE.

 

The rational and practical nature of the papyrus is illustrated in the 48 cases. The papyrus begins by addressing injuries to the head, and continues with treatments for injuries to neck, arms and torso. The title of each case details the nature of trauma, such as Practices for a gaping wound in his head, which has penetrated to the bone and split the skull. Next, the examination provides further details of the trauma. The diagnosis and prognosis follow the examination. Last, treatment options are offered. In many of the cases, explanations of trauma are included to provide further clarity.

 

Among the treatments are closing wounds with sutures (for wounds of the lip, throat, and shoulder), preventing and curing infection with honey, and stopping bleeding with raw meat. Immobilization is advised for head and spinal cord injuries, as well as other lower body fractures. The papyrus also describes anatomical observations. It contains the first known descriptions of the cranial sutures, the meninges, the external surface of the brain, the cerebrospinal fluid, and the intracranial pulsations. The procedures of this papyrus demonstrate an Egyptian level of knowledge of medicines that surpassed that of Hippocrates, who lived 1000 years later. Due to its practical nature and the types of trauma investigated, it is believed that the papyrus served as a textbook for the trauma that resulted from military battles.

 

Edwin Smith purchased the papyrus in Luxor, Egypt in 1862, from an Egyptian dealer named Mustafa Agha. The papyrus was in the possession of Smith until his death, when his daughter donated the papyrus to New York Historical Society. From 1938 through 1948, the papyrus was at the Brooklyn Museum. In 1948, the New York Historical Society and the Brooklyn Museum presented the papyrus to the New York Academy of Medicine, where it remains today.

 

The first translation of the papyrus was by James Henry Breasted, with the medical advice of Dr. Arno B Luckhardt, in 1930 Breasted¹s translation changed the understanding of the history of medicine. It demonstrates that Egyptian medical care was not limited to the magical modes of healing demonstrated in other Egyptian medical sources. Rational, scientific practices were used, constructed through observation and examination.

 

From 2005 through 2006, the Edwin Smith Papyrus was on exhibition at the Metropolitan Museum of Art in New York. James P. Allen, curator of Egyptian Art at the museum, published a new translation of the work, coincident with the exhibition. This was the first complete English translation since Breasted¹s in 1930. This translation offers a more modern understanding of hieratic and medicine.

First-in-Human Testing of a Wirelessly Controlled Drug Delivery Microchip

 

 

Human parathyroid hormone fragment [hPTH(1-34)] is the only approved anabolic osteoporosis treatment, but requires daily injections, making patient compliance an obstacle to effective treatment. Furthermore, a net increase in bone mineral density requires intermittent or pulsatile hPTH(1-34) delivery, a challenge for implantable drug delivery products.

 

As a result, a study published online in Science Translational Medicine Rapid Publication (16 February 2012), reports the results of a clinical trial where a microchip-based device, containing discrete doses of lyophilized hPTH(1-34), were implanted in 8 osteoporotic postmenopausal women for 4 months. The device was wirelessly programmed to release doses once daily for up to 20 days. A computer-based programmer, operating in the Medical Implant Communications Service band, established a bidirectional wireless communication link with the implant to program the dosing schedule and receive implant status confirming proper operation. Each woman subsequently received hPTH(1-34) injections in escalating doses and the pharmacokinetics, safety, tolerability, and bioequivalence of hPTH(1-34) were assessed.

 

Results showed that device dosing produced similar pharmacokinetics to multiple injections, and had lower coefficients of variation. Bone marker evaluation indicated that daily release from the device increased bone formation. There were no toxic or adverse events due to the device or drug, and patients stated that the implant did not impact quality of life.

Intracoronary Cardiosphere-Derived Cells For Heart Regeneration After Myocardial Infarction

 

According to an article published in The Lancet, Early Online Publication (14 February 2012), infusion of cardiosphere-derived stem cells (CDCs) into patients who had had heart attacks can help regenerate healthy heart muscle.

 

For the study, between May 5, 2009, and Dec 16, 2010, the CADUCEUS (CArdiosphere-Derived aUtologous stem CElls to reverse ventricUlar dySfunction) study assessed 25 patients, average age of 53 years, who experienced an MI 2-4 weeks prior (with left ventricular ejection fraction of 25 to 45%). Of the 25 patients, eight received standard care while 17 received infusions of CDCs, which are cardiac stem cells created using the patient’s own heart tissue. The primary endpoint was the proportion of patients at six months who died due to ventricular tachycardia, ventricular fibrillation, sudden unexpected death or had an MI after cell infusion, new cardiac tumor formation on MRI, or a major adverse cardiac event – defined as composite of death and hospital admission for heart failure or non-fatal recurrent MI.

 

The procedure is minimally invasive and involves removing pieces of living heart muscle around half the size of a raisin using a catheter under local anesthetic; this tissue was then used to create the supply of cardiac stem cells. Each patient received an infusion of around 12 to 25 million of his or her own stem cells during a second minimally invasive procedure.

 

Results showed that patients who had the stem cell infusion saw their scar size drop from 24% to 12% of the heart on average (a reduction by about 50%), while controls saw no reduction in scar size. Changes in end-diastolic volume, end-systolic volume and left ventricular ejection fraction did not differ between groups by six months. Four patients (24%) in the stem cell group had serious adverse events compared with one control (13%), although of the four events in the stem cell group, only one was regarded as possibly related to the treatment. One patient developed recurrent MI and four patients received additional cardiac interventions (including one patient who had coronary revascularization and three who needed implantation of prophylactic defibrillators) in the CDC group.

 

The authors concluded that intracoronary infusion of autologous CDCs after MI is safe, warranting the expansion of such therapy to phase II study. The unprecedented increases we noted in viable myocardium, which are consistent with therapeutic regeneration, merit further assessment of clinical outcomes.

Midlife Psychological Distress Associated With Late-Life Brain Atrophy and White Matter Lesions

 

 

Long-standing psychological distress increases the risk of dementia, especially Alzheimer’s disease. As a result, a study published in Psychosomatic Medicine (2012;74: 120-125), was performed to examine the relationship between midlife psychological distress and late-life brain atrophy and white matter lesions (WMLs), which are common findings on neuroimaging in elderly subjects.

 

For the study, a population-based sample of 1,462 women, aged 38 to 60 years, was examined in 1968, with subsequent examinations in 1974, 1980, 1992, and 2000. Computed tomography (CT) of the brain was done in 379 survivors in 2000, and of those, 344 had responded to a standardized question about psychological distress in 1968, 1974, and 1980. WMLs, cortical atrophy, and central atrophy (ventricular sizes) were measured at CT scans.

 

Results showed that compared with women reporting no distress, those reporting frequent or constant distress at one examination or more (in 1968, 1974, and 1980) more often had moderate-to-severe WMLs (odds ratio = 2.39) and moderate-to-severe temporal lobe atrophy (odds ratio = 2.51) on brain CT in 2000. Frequent/constant distress was also associated with central brain atrophy, that is, higher bicaudate ratio, higher cella media ratio, and larger third-ventricle width.

 

According to the authors, long-standing psychological distress in midlife increases risks of cerebral atrophy and WMLs on CT in late life, but more studies are needed to confirm these findings and to determine potential neurobiological mechanisms of these associations.

TARGET HEALTH excels in Regulatory Affairs. Each week we highlight new information in this challenging area.

 

 

FDA Approves Korlym for Patients with Endogenous Cushing’s Syndrome

 

 

Endogenous Cushing’s syndrome is a serious, debilitating and rare multisystem disorder. It is caused by the overproduction of cortisol (a steroid hormone that increases blood sugar levels) by the adrenal glands. This syndrome most commonly affects adults between the ages of 25 and 40.

 

FDA approved Korlym (mifepristone) to control high blood sugar levels (hyperglycemia) in adults with endogenous Cushing’s syndrome. who have type 2 diabetes or glucose intolerance and are not candidates for surgery or who have not responded to prior surgery. Korlym should never be used (contraindicated) by pregnant women. About 5,000 patients will be eligible for Korlym treatment, which received an orphan drug designation by the FDA in 2007. Korlym blocks the binding of cortisol to its receptor. It does not decrease cortisol production but reduces the effects of excess cortisol, such as high blood sugar levels.Prior to FDA’s approval of Korlym, there were no approved medical therapies for the treatment of endogenous Cushing’s syndrome.

 

The safety and efficacy of Korlym in patients with endogenous Cushing’s syndrome was evaluated in a clinical trial with 50 patients. A separate open-label extension of this trial is ongoing. Additional evidence supporting the agency’s approval included several safety pharmacology studies, drug-drug interaction studies and published scientific literature. Results from the clinical trial showed that patients experienced significant improvement in blood sugar control during Korlym treatment, including some patients who had marked reductions in their insulin requirements. Improvements in clinical signs and symptoms were reported by some patients.

 

The most common side effects in clinical trials were nausea, fatigue, headache, arthralgia, vomiting, swelling of the extremities, dizziness and decreased appetite. Other side effects included adrenal insufficiency, low potassium levels, vaginal bleeding and a potential for heart conduction abnormalities. Certain drugs used in combination with Korlym may increase its drug level. Health care professionals must be aware of the potential for drug-drug interactions and adjust dosing or avoid using certain drugs with Korlym.

 

Korlym should never be used by pregnant women. Although pregnancy is an extremely rare, occurrence in Cushing’s syndrome patients because of the suppressive effect of excess cortisol on female reproductive function, Korlym will carry a Boxed Warning advising health care professionals and patients that the therapy will terminate a pregnancy.

 

The FDA has determined that a Risk Evaluation and Mitigation Strategy (REMS) is not necessary for Korlym to ensure that the benefits outweigh the risks for patients with endogenous Cushing’s syndrome. Several factors were considered in this determination including the following:

 

  • There are no other approved medical therapies for this debilitating form of Cushing’s syndrome and very sick patients would suffer if impediments to access were imposed.
  • The number of Cushing’s syndrome patients who will require treatment with Korlym is small, with an estimated 5,000 patients being eligible for treatment.
  • The number of health care professionals in the United States who would potentially prescribe Korlym is very small and highly specialized. They are familiar with the risks of Korlym treatment in the endogenous Cushing’s syndrome population and frequently monitor patient status.
  • The risks of Korlym treatment in the intended population can be managed through physician and patient labeling. The risks associated with Korlym will be outlined in a medication guide for patients.

 

The company has voluntarily proposed distributing Korlym through a central pharmacy to ensure the timely, convenient and appropriate delivery of the drug to Cushing’s patients or to the health care institutions where this therapy may be initiated. Most retail pharmacies are unlikely to keep adequate supplies of the drug for this rare condition and central distribution will give patients with Cushing’s syndrome better access to Korlym.

 

Korlym is manufactured by Corcept Therapeutics of Menlo Park, Calif.

Let the “Sunshine” In…

 

 

By Mark L. Horn, MD, MPH, Chief Medical Officer, Target Health Inc.

 

 

This past Friday was the final opportunity to comment on CMS’ proposed rule implementing the “Sunshine” provisions in the Affordable Care Act. Briefly, and with acknowledged “editorializing”, these provisions seem predicated on the assumption that there are irremediable conflicts of interest created by payments from industry to providers (physicians, teaching hospitals, and certain others) which they seek to address by creating a searchable database of most (there are some exemptions) of these payments. The presumed objective is captured in a famous quote from Supreme Court Justice Louis Brandeis…”Sunlight (per Justice Brandeis) is the best disinfectant”.

 

Interestingly, the financial penalties for non-compliance fall on manufacturers; providers are offered the chance to review the data before these go ‘live’ on the web, but apparently suffer reputational risk only, e.g., no financial liability, for failure to examine and correct the information. The (admittedly unverifiable) assumption seems to be that the potential embarrassment of receiving support from product manufacturers will prove sufficient motivation for providers to review and correct erroneous entries or, in the extreme, entirely avoid engaging with industry.

 

The rule and its proposed implementation have, unsurprisingly, proven contentious. It’s worth asking if, in addition to the basic work and associated expense involved in collecting and reporting the data, there are potential downsides and unintended consequences.

 

There have indeed been (too) many highly publicized allegations of financially motivated provider-manufacturer misbehavior. At the same time, both society and the overall business community have come to appreciate that more interaction and communication are generally better than less, especially in highly technical matters. Given that, might the medicine prescribed in this case, which may well result in diminished interactions among industry and the medical and scientific communities, reflect (to borrow and slightly twist a cliché) an example of “tough cases making bad law”.

 

Among the reportable types of compensation (limiting this discussion to issues most relevant to Target Health clients) are payments to investigators conducting clinical research. Presumably, (and again, acknowledging that some will disagree) many readers of On-Target would consider this an honorable and societally beneficial activity. Therefore, the question emerges; does the proposed reporting requirement create a risk to the research enterprise? Do we, by potentially embarrassing providers who participate in clinical research, risk meaningfully diminishing participation in the process? If so, does it matter; is the risk of losing investigators real, and is it justified by the benefits of broad disclosure?

 

Finally, if the risk is justified is there anything we can do to mitigate it?

 

Some creative thinking is justified.

 

Imagine if industry supported a public education effort focused on the value of clinical trials overall and specifically the critical importance of participation by motivated, well trained physicians. The goal is to make these relationships with industry sources of pride, not shame. Imagine if patients actively sought out clinical investigators for care, if physician investigators and teaching hospitals conducting trials proactively directed patients to the CMS website confirming their role in industry sponsored clinical investigations. That would be, for all parties, a salutary outcome from this rule, one which supports the goal of transparency while concurrently acknowledging the virtue of (at least some) industry-physician relationships.

 

An idea, perhaps, for industry trade associations to consider?