Target Health is pleased to announce that Dr. Mitchel will be attending the FDA public hearing on April 23, 2012, on the topic of Modernizing the Regulation of Clinical Trials and Approaches to Good Clinical Practice. The hearing will take place at FDA White Oak Campus, 10903 New Hampshire Ave, Building 31, Room 1503, Silver Spring, Maryland 20993.
The purpose of this public hearing is to obtain input from interested persons on FDA’s scope and direction in modernizing the regulations, policies, and practices that apply to the conduct of clinical trials of FDA-regulated products. The goal is to solicit public input on FDA’s efforts to modernize the regulatory framework that governs clinical trials and approaches to good clinical practice (GCP), including encouraging the use of innovative models that may enhance the effectiveness and efficiency of the clinical trial enterprise.
Please let us know if you will be attending.
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
Fountain with Baron Munchhausen. on his cut-into half horse, in front of the Münchhausen
Museum at Bodenwerder
Book illustration: Baron Münchhausen Riding on a Canon Ball
Munchausen (MOON-chow-zun) syndrome is a serious mental disorder in which someone with a deep need for attention pretends to be 1) ___ or gets sick or injured on purpose. People with Munchausen syndrome may make up symptoms, push for risky operations, or try to rig laboratory test results to try to win sympathy and concern. Munchausen syndrome belongs to a group of conditions, called factitious disorders, that are either made up or self-inflicted. Factitious disorders can be psychological or physical. Munchausen syndrome refers to the most severe and chronic physical form of factitious 2) ___. Munchausen syndrome is a mysterious and hard to treat disorder. However, medical help is critical for preventing serious injury and even death caused by the self-harm typical of Munchausen 3) ___.
It is also sometimes known as hospital addiction syndrome or hospital hopper syndrome. Nurses and doctors sometimes refer to them as frequent flyers, because they return to the 4) ___ just as frequent flyers return to the airport. However, there is discussion to reclassify them as somatoform disorder in the DSM-5 as it is unclear whether or not people are conscious of drawing attention to themselves.
Munchausen syndrome is related to Munchausen syndrome by proxy (MSbP/MSP), which refers to the abuse of another being, typically a child, in order to seek attention or sympathy for the 5) ___.
In Munchausen syndrome, the affected person exaggerates or creates 6) ___ of illnesses in themselves to gain investigation, treatment, attention, sympathy, and comfort from medical personnel. In some extreme cases, people suffering from Munchausen’s syndrome are highly knowledgeable about the practice of medicine and are able to produce symptoms that result in lengthy and costly medical analysis, prolonged hospital stay and unnecessary operations. The role of “patient” is a familiar and comforting one, and it fills a psychological need in people with Münchausen’s. It is distinct from hypochondriasis in that patients with Munchausen syndrome are aware that they are exaggerating, whereas sufferers of 7) ___ believe they actually have a disease. Risk factors for developing Munchausen syndrome include childhood traumas and growing up with parents/caretakers who were emotionally unavailable due to illness or emotional problems. Arrhythmogenic Munchausen syndrome describes individuals who simulate or stimulate cardiac arrhythmias to gain medical attention.
A similar behavior called Munchausen syndrome by proxy has been documented in the parent or guardian of a child. The adult ensures that his or her child will experience some medical affliction, therefore compelling the child to suffer treatment for a significant portion of their youth in hospitals. Furthermore, a disease may actually be initiated in the child by the parent or 8) ___. This condition is considered distinct from Munchausen syndrome. In fact, there is growing consensus in the pediatric community that this disorder should be renamed “medical abuse” to highlight the real harm caused by the deception and to make it less likely that a perpetrator can use a psychiatric defense when real harm is done. Parents who perpetrate this abuse are often affected by concomitant psychiatric problems like depression, spouse abuse, psychopathy, or psychosis. In rare cases, multiple children in one family may be affected either directly as 9) ___ or as witnesses who are threatened to keep them silent.
ANSWERS: 1) sick; 2) disorder; 3) syndrome; 4) hospital; 5) abuser; 6) symptoms; 7) hypochondriasis; 8) guardian; 9) victims
Baron Karl Friedrich Munchausen
(1720-1797) Baron Karl Friedrich Hieronymus, Freiherr von Munchhausen, a German nobleman and teller of tall tales, joined the Russian military and served until 1750, in particular taking part in two campaigns against the Ottoman Turks. In 1750, he was named a Rittmeister, a cavalry captain.
Returning home, Munchhausen supposedly told a number of outrageously farfetched stories about his adventures. The stories about Munchhausen were first collected and published by an anonymous author in 1781. Rudolf Raspe later published “stories” under the title of The Surprising Adventures of Baron Munchhausen.
In 1951, Richard Asher MD was the first to describe a pattern of self-harm, where individuals fabricated histories, signs, and symptoms of illness. Remembering Baron Munchhausen, Asher named this condition Munchausen’s Syndrome in his article in The Lancet in February 1951, quoted in his obituary in the British Medical Journal: “Here is described a common syndrome which most doctors have seen, but about which little has been written. Like the famous Baron von Munchausen, the persons affected have always travelled widely; and their stories, like those attributed to him, are both dramatic and untruthful. Accordingly the syndrome is respectfully dedicated to the Baron, and named after him.”
It is not clear how much of the story material derives from the Baron himself, but it is known that the majority of the stories are based on folktales that had been in circulation for many centuries before Munchhausen’s birth. The historical Baron Munchhausen was said to be deeply annoyed that his name was dragged into the public consciousness as the lying baron through the publication of stories under his name.
Women Spend Longer in Labor Now Than 50 Years Ago
According to an article published online in the American Journal of Obstetrics and Gynecology (12 March 2012), an analysis of nearly 140,000 deliveries, indicated that women now take longer to give birth today than 50 years ago, The study could not identify all of the factors that accounted for the increase, but concluded that the change is likely due to changes in delivery room practice. The study authors called for further research to determine whether modern delivery practices are contributing to the increase in labor duration.
The study compared data from nearly 40,000 deliveries between 1959 and 1966 with records of almost 100,000 deliveries that took place in 2002 through 2008. Data from the recent deliveries were collected through the NICHD-supported Consortium on Safe Labor.
It was found that the first stage of labor had increased by 2.6 hours for first-time mothers. For women who had previously given birth, this early stage of labor took two hours longer in recent years than for women in the 1960s. The first stage of labor is the stage during which the cervix dilates, before active pushing begins.
Infants born in the contemporary group also were born five days earlier, on average, than were those born in the 1960s, and tended to weigh more. The women in the contemporary group tended to weigh more than did those who delivered in the 1960s. For the contemporary group, the average body mass index before pregnancy was 24.9, compared with 23 for the earlier generation. Body mass index is a measure of body fat based on height and weight. At the time they gave birth, the mothers in the contemporary group were about four years older, on average, than those in the group who gave birth in the 1960s.
Among the change in delivery practice was an increase in the use of epidural anesthesia, the injection of pain killers into the spinal fluid, to decrease the pain of labor. For the contemporary group, epidural injections were used in more than half of recent deliveries, compared with 4% of deliveries in the 1960s. The study authors noted that epidural anesthesia is known to increase delivery time, but said it doesn’t account for all of the increase.
Doctors in the early 2000s also administered the hormone oxytocin more frequently (in 31% of deliveries, compared with 12% in the 1960s), the researchers found. Oxytocin is given to speed up labor, often when contractions seem to have slowed and its use should be expected to shorten labor times.
Other differences between the two groups reflect changes in later stage delivery practices. For example, in 1960s-era deliveries the use of episiotomy (surgical incision to enlarge the vaginal opening during delivery), and the use of forceps, surgical instruments used to extract the baby from the birth canal, was notably more common. In current practice, doctors may intervene when labor fails to progress. This could happen if the dilation of the cervix slows or the active phase of labor stops for several hours, In these cases, intervention can include administering oxytocin or performing a cesarean delivery. In fact, the study found that the rate of cesarean delivery was four times higher today than it was 50 years ago (12% vs. 3%).
The women in the contemporary cohort had an average pre-pregnancy BMI of 24.9. A BMI of 25 is considered overweight. Overweight and obesity raise the risk of pregnancy complications for mother and baby. Women who are overweight or obese and who would like to become pregnant should speak with their health care provider about losing weight before becoming pregnant.
Targeted Investigational Drug Induces Responses in Aggressive Lymphomas
Lymphomas are the fifth most common form of cancer. They are caused by an abnormal proliferation of white blood cells, can occur at any age, and are often marked by lymph nodes that are larger than normal, fever, and weight loss. Diffuse large B-cell lymphomas (DLBCL), which were studied in this trial, are aggressive cancers that grow rapidly and represent 30% to 40% of newly diagnosed lymphomas. DLBCL originates from B cells, which play a crucial role in the body’s immune response.
There have been no major advances in the treatment of DLBCL in more than a decade. However, important advances have been made in understanding that this disease is comprised of at least three molecular subtypes, each derived from B cells at unique stages in their development. The activated B-cell (ABC) subtype of DLBCL accounts for approximately 40% of cases and has the poorest clinical outcome with current therapy.
Recent genetic studies have revealed that chronic activity of receptors that sit on the surface of B cells play an important role in the progression of ABC lymphomas. In normal B cells, these B-cell receptors help the cells recognize infections. In malignant B cells of ABC lymphomas, these receptors provide crucial signals that promote tumor cell survival. Over one-fifth of ABC tumors have mutations that alter the activity of the B-cell receptor. Based on these findings, researchers looked for ways to target B-cell receptor signaling therapeutically. This research identified the enzyme Bruton’s tyrosine kinase (BTK) as a key element in the B-cell receptor pathway that is required to maintain the survival of ABC lymphoma cells.
Preliminary results from clinical trials in a subtype of lymphoma showed that for a number of patients whose disease was not cured by other treatments, the drug ibrutinib can provide significant anti-cancer responses with modest side effects. The data were presented as part of the opening plenary session at the American Association of Cancer Research (AACR) Annual Meeting 2012 on April 1.
Based on this molecular research, the investigators chose to use the drug ibrutinib (formerly PCI-32765), a potent inhibitor of BTK, in their clinical trials. Ibrutinib is an oral, highly specific and irreversible inhibitor of the BTK enzyme. Pharmacyclics Inc., Sunnyvale, Calif., and Janssen Research and Development, L.L.C., Horsham, Pa., are developing the drug to target B-cell malignancies, including various forms of leukemia, lymphoma and multiple myeloma.
Ibrutinib was first evaluated in a pilot trial at NCI in ABC DLBCL, and is now being evaluated in an ongoing multicenter study in DLBCL. Results from the pilot trial and individual cases from the ongoing trial indicate that the use of the single agent pill form of ibrutinib can elicit major anti-lymphoma effects with minimal side effects.
Participants in these studies were given ibrutinib as a pill at a fixed dose of 560 milligrams daily until the disease progresses. Ibrutinib induced multiple responses including some complete remissions in ABC lymphomas. Remissions were also observed in patients with non-ABC DLBCL, suggesting a broader role for the B-cell receptor pathway in this type of lymphoma. A final analysis will provide additional insights into the safety and efficacy of ibrutinib in the treatment of DLBCL.
Arsenic Turns Stem Cells Cancerous, Spurring Tumor Growth
Stem cells are unique in the body. They stay around for a long time and are capable of dividing and renewing themselves. “Most cancers take 30 or 40 years to develop,” said Linda Birnbaum, Ph.D., director of NIH’s NIEHS and NTP. “It makes sense that stem cells may play a role in the developmental basis of adult disease. We know that exposures to toxicants during development and growth can lead to diseases later in life.”
Inorganic arsenic, which affects the drinking water of millions of people worldwide, has been previously shown to be a human carcinogen. A growing body of evidence suggests that cancer is a stem-cell based disease. Normal stem cells are essential to normal tissue regeneration, and to the stability of organisms and processes. But cancer stem cells are thought to be the driving force for the formation, growth, and spread of tumors. Now, researchers at the National Institutes of Health have discovered how exposure to arsenic can turn normal stem cells into cancer stem cells and spur tumor growth. The paper is online in Environmental Health Perspectives (4 April 2012.
The authors had shown previously that normal cells become cancerous when they are treated with inorganic arsenic. This new study shows that when these cancer cells are placed near, but not in contact with normal stem cells, the normal stem cells very rapidly acquire the characteristics of cancer stem cells. It demonstrates that malignant cells are able to send molecular signals through a semi-permeable membrane, where cells can’t normally pass, and turn the normal stem cells into cancer stem cells.
This reveals a potentially important aspect of arsenic carcinogenesis and may help explain observances by researchers working with arsenic that arsenic often causes multiple tumors of many types to form on the skin or inside the body. The authors started working with stem cells about five years ago using a prostate stem cell line, not embryonic stem cells.
Next, the laboratory team will look to see if this finding is unique to arsenic or if it is applicable to other organic and inorganic carcinogens.
TARGET HEALTH excels in Regulatory Affairs. Each week we highlight new information in this challenging area
FDA Approves Omontys to Treat Anemia in Adult Patients on Dialysis
The FDA has approved Omontys (peginesatide) to treat anemia, a condition in which the body does not have enough healthy red blood cells, in adult dialysis patients who have chronic kidney disease (CKD). Omontys is a new erythropoiesis-stimulating agent (ESA) that aids in the formation of red blood cells. It works by stimulating the bone marrow to produce more red blood cells, usually measured as hemoglobin levels, to reduce the need for transfusions in patients with CKD. Omontys is administered as a once-a-month injection.
Two randomized, active-controlled, open-label, multi-center clinical trials demonstrated the safety and efficacy of Omontys in patients with CKD who were on dialysis. The trials randomly selected a total of 1,608 patients with hemoglobin levels initially stabilized by ESA to receive either Omontys once monthly or to continue their current ESA (epoetin) treatment. Results showed Omontys was as safe and effective as epoetin in maintaining hemoglobin levels within the studies’ pre-specified range of 10 to 12 grams per deciliter.
The most common side effects observed in 10% or more of dialysis patients treated with Omontys were diarrhea, vomiting, high blood pressure (hypertension) and joint, back, leg or arm pain (arthralgia).
Omontys should not be used in patients with CKD who are not receiving dialysis or in patients with cancer–related anemia, according to the FDA-approved labeling. It also should not be used as a substitute for red blood cell transfusions in patients who require immediate correction of anemia. Omontys has not been shown to improve symptoms of anemia, physical functioning or health-related quality of life in patients with CKD on dialysis.
The FDA approved Omontys with a Risk Evaluation and Mitigation Strategy (REMS), which added safety measures consisting of educational elements for health care professionals and a requirement to assess drug use data.
Omontys is marketed by Affymax Inc. of Palo Alto, Calif.