FDA Meeting on Direct Data Entry and Risk-Based Monitoring



As part of Target Health’s commitment to transparency on its programs using risk-based monitoring and direct data entry integrated with Target e*CTR® (eClinical trial record), we would like to share the results of a recent end-of phase 2 meeting where the topic of risk-based monitoring plan, coordinated with direct data entry, was discussed. As part of our Briefing Document, it was requested that the FDA review division invite a representative from the Office of Scientific Investigations (OSI), which they did.


Under the Regulatory section of the Briefing Document, we wrote: “As was done in the Phase 2 study, the pivotal trial will utilize Target e*CTR (eClinical Trial Record) for direct data entry and the generation of the original data at the time of the patient visit. Target e*CTR allows for the clinical sites to enter clinical trial data at the time of the patient encounter, which are then transmitted directly into a secure trusted 3rd party environment prior to the data reaching the EDC database. In this way, original data entered at the time of the patient visit can be maintained in electronic format in lieu of paper records. The system is validated, 21 CFR Part 11 compliant, and fully integrated with Target e*CRF (EDC). The clinical development program will also utilize Target Document for the eTMF (trial master file) for document management and control for both the sponsor and the clinical sites. The system allows for electronic signatures and document control. Target Document is being used in the phase 2 study in lieu of paper records. The system is validated and 21 CFR Part 11 compliant. FDA can be given access to these software products and the EDC application at any point during the study as well as during onsite and offsite inspections. Does FDA agree that these systems are acceptable for data capture in the pivotal trial?”


At the meeting, we stated verbally that: “Our goal is to conduct the study, in part, by being compliant with the 2010 Draft eSource and 2011 Draft Risk-Base Monitoring Guidances. Similar to what we did in the initial Phase 2 study, we plan to use validated software products that allow for 1) direct data entry of clinical trial data into our EDC system, with the creation of an original record prior to the data being entered into the EDC database; 2) the use of an online eTMF; 3) the use of online monitoring reports; and 4) the performance of risk-based monitoring. We have included our overall plans in the Quality Section of the protocol as recommended by the guidances and look forward to feedback from the Agency.”


The FDA review division agreed that any and all questions related to the Quality Section of the protocol should be sent to the review division under the IND and they would forward the request to the OSI for their feedback. We were told to make it very clear in our IND submission what specific questions and specific documents were to be forward to OSI.


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

BioEngineering: Cat Brain Provides a Step Toward the Electronic Equivalent


A cat can recognize a face faster and more efficiently than a supercomputer. That’s one reason a feline brain is the model for a biologically-inspired computer project involving the University of Michigan. (Credit: iStockphoto/Jonny Kristoffersson)



A cat can recognize a face faster and more efficiently than a supercomputer. That’s one reason a 1) ___ brain is the model for a biologically-inspired computer project involving the University of Michigan (U-M). U-M computer engineer Wei Lu has taken a step toward developing this revolutionary type of machine that could be capable of learning and recognizing, as well as making more complex decisions and performing more tasks simultaneously than conventional 2) ___ can. Lu previously built a “memristor,” a device that replaces a traditional transistor and acts like a biological synapse, remembering past voltages it was subjected to. Now, he has demonstrated that this memristor can connect conventional circuits and support a process that is the basis for memory and learning in 3) ___ systems. A paper on the research is published online in Nano Letters.


“We are building a computer in the same way that nature builds a brain,” said Lu, an assistant professor in the U-M Department of Electrical Engineering and Computer Science. “The idea is to use a completely different paradigm compared to conventional computers. The cat brain sets a realistic goal because it is much simpler than a 4) ___ brain but still extremely difficult to replicate in complexity and efficiency.”


Today’s most sophisticated supercomputers can accomplish certain tasks with the brain functionality of a cat, but it’s a massive machine with more than 140,000 central processing units and a dedicated power supply. And it still performs 83 times slower than a 5) ___ brain, Lu wrote in his paper. In a mammal’s brain, neurons are connected to each other by synapses, which act as reconfigurable switches that can form pathways linking thousands of neurons. Most importantly, 6) ___ remember these pathways based on the strength and timing of electrical signals generated by the neurons. In a conventional computer, logic and memory functions are located at different parts of the circuit and each computing unit is only connected to a handful of neighbors in the circuit. As a result, conventional computers execute code in a 7) ___ fashion, line by line, Lu said. They are excellent at performing relatively simple tasks with limited variables.


But a brain can perform many operations simultaneously, or in parallel. That’s how we can recognize a face in an instant, but even a supercomputer would take much, much 8) ___ and consume much more energy in doing so. So far, Lu has connected two electronic 9) ___ with one memristor. He has demonstrated that this system is capable of a memory and learning process called “spike timing dependent plasticity.” This type of plasticity refers to the ability of connections between neurons to become stronger based on when they are stimulated in relation to each other. Spike timing dependent plasticity is thought to be the basis for memory and learning in mammalian brains. “We show that we can use voltage timing to gradually increase or decrease the electrical conductance in this memristor-based system. In our brains, similar changes in synapse 10) ___ essentially give rise to long term memory,“ Lu said. The next step is to build a larger system, Lu said. His goal is to achieve the sophistication of a 11) ___ in a machine the size of a two-liter beverage container. That could be several years away.


Lu said an electronic analog of a cat brain would be able to think intelligently at the cat level. For example, if the task were to find the shortest route from the front door to the sofa in a house full of furniture, and the computer knows only the shape of the sofa, a conventional machine could accomplish this. But if you moved the sofa, it wouldn’t realize the adjustment and find a new path. That’s what engineers hope the cat brain computer would be capable of. The project’s major funder, DARPA or, 12) ___ ___ ___ ___ ___, and the National Science Foundation, isn’t interested in sofas. But this illustrates the type of learning the machine is being designed for.


ANSWERS: 1) feline; 2) computers; 3) biological; 4) human; 5) cat’s; 6) synapses; 7) linear; 8) longer; 9) circuits; 10) conductance; 11) supercomputer; 12) Defense Advanced Research Projects Agency

Hospital Tests Reveal the Secrets of an Egyptian Mummy


Images from the recent CT scans of the mummy show that the child still had some of its baby teeth, with adult teeth coming in. (Credit: Photo by David Hunt, Smithsonian Institution)



Images from the recent CT scans of the mummy show that the child still had some of its baby teeth, with adult teeth coming in. (Credit: Photo by David Hunt, Smithsonian Institution)


An ancient Egyptian mummy has had quite an afterlife, traveling more than 6,000 miles, spending six decades in private hands, and finally, in 1989, finding a home at the World Heritage Museum (now the Spurlock Museum) at the University of Illinois. The mummy’s travels did not end there, however. It has made two trips to a local hospital – once in 1990 and again this year, 2011 – for some not-so-routine medical exams.


Egyptologists, a radiologist, a pathologist, a physical anthropologist and a mummy expert are using the best diagnostic tools available to learn about the mummy without unwrapping its red linen shroud or cutting into it. The team will discuss its findings during a symposium Nov. 2 at the museum in Urbana, Ill. The first round of tests in 1990 included X-rays and CT scans, as well as an analysis of tiny fragments of cloth, insects and hardened resins collected from the fraying base of the mummy. Dr. Joseph Barkmeier, medical director of diagnostic services and regional outreach at Carle Foundation Hospital and Physician Group in Urbana, conducted the CT scans at the hospital. He repeated the scans this year at Carle with much-improved CT technology. “Medical diagnostic technology has experienced tremendous advancements in the past two decades,“ Barkmeier said. “Image resolution is nearly 10 times greater than it was when we first imaged the mummy in 1990, and we can reconstruct images faster and view them from multiple vantage points.“


The scans and an analysis of the materials used in embalming (including carbon-14 dating of a wooden plank that supports the body) found that the mummy was a child of a wealthy family from the Roman period of ancient Egypt. Examining a digitized mummy constructed from cross-sectional CT scans is similar to actually dissecting it – with some notable limitations, said Sarah Wisseman, project coordinator of the mummy studies and director of the Program on Ancient Technologies and Archaeological Materials (ATAM) at the Illinois State Archaeological Survey. Wisseman is the author of “The Virtual Mummy,“ a book about the research.


The scans reveal the bone structure and also show that the embalmers left the brain, the heart and lungs in the body, she said. The images also offer insight into the materials used to stabilize, wrap and “fill out“ the body. But they do not provide fine details of the soft tissues that remain, she said. David Hunt, of the Smithsonian Institution’s National Museum of Natural History, observed that the child still had some of its baby teeth, with adult teeth coming in. This and evidence that the long bones were still growing at the time of death indicate that the child was 7 to 9 years old, Wisseman said.


Several signs — including a cracked skull with no evidence of bleeding and the detection of carrion beetles in the body — suggest that the embalmers “did a crummy job or this body was lying around for a while before it was treated,“ Wisseman said. If the child died during an epidemic there could have been a lot of corpses to deal with, she said, causing delays or forcing the embalmers to rush. “All of the evidence, however, suggests that this is a child from a wealthy family,“ she said. “They’re using expensive red pigment from Spain. They’re using gold gilt decoration. This is a fairly high-class kid.“


Despite the high-tech probing, the mummy has maintained some of its secrets. Its hands are positioned in front of its collapsed pelvis, hiding any evidence of its sex. And DNA tests of a sample collected from the damaged region near its base have yielded no definitive results so far. There are some “tantalizing“ clues to the child’s gender in the face portrait attached to the mummy, Wisseman said, but such images can be misleading. “There’s a suggestion around the portrait of a tunic with a stripe on it. This alone would suggest that the child inside is a boy,” she said. “But there are other mummies that have one person depicted on the outside and then you discover it’s a different gender or even an animal instead of a human, so you can’t tell a book by its cover.“ The CT scans also revealed something that might be a lock of hair on one side of the child’s head, Wisseman said.


“In the Roman period in Egypt, around A.D. 100, we do have examples of Roman face portraits with a shaved head and then a lock of hair on one side,“ she said. Boys had the lock on one side, girls on the other. But the evidence is not conclusive. “We may not ever know whether the child was male or female,“ she said. “And we still don’t know the cause of death.“ The symposium, called “The Return of the Mummy: New Imaging Results on the Spurlock Museum’s Egyptian Mummy,” is at the Knight Auditorium, Spurlock Museum, 600 S. Gregory St., Urbana.


Story Source: The above story is reprinted from materials provided by University of Illinois at Urbana-Champaign.

Wood Stove Intervention Can Reduce Childhood Pneumonia



Pneumonia kills almost 1.6 million children each year. Though childhood deaths from pneumonia are relatively uncommon in the United States, it kills more children worldwide than any other disease. Open fires used for heating and cooking are thought to be a major cause of pneumonia.


According to a study published in The Lancet (2011;378: 1717-1726), cooking stoves with chimneys can lower exposure to indoor wood smoke and reduce the rate of severe pneumonia by 30% in children less than 18 months of age. The study showed that rates of severe childhood pneumonia were significantly reduced in households provided with a wood stove connected to a chimney, compared with homes where open, indoor wood cooking fires were used. The lead researchers at the University of California, Berkeley, report that carbon monoxide exposure levels were reduced 50% on average in the homes equipped with chimneys.


The NIH Randomized Exposure Study of Pollution Indoors and Respiratory Effects (RESPIRE) trial included a total of 534 households in rural Guatemala with a pregnant woman or young infant. The study participants were randomly assigned to receive a locally developed cookstove with a chimney or to continue cooking using traditional open wood fires. In all, 265 children were from the chimney-stove homes and 253 children were in the control homes. Trained field workers visited the homes every week for two years to record the children’s health status. Sick children with cough and fast breathing were referred to physicians.


Although the study did not significantly reduce the total number of diagnosed childhood pneumonia cases, the reduction in severe pneumonia would likely result in reduced childhood mortality, according to the authors.

Intensive Therapy Halves Kidney Disease in Type 1 Diabetes



Nearly 26 million Americans have diabetes. In adults, type 1 diabetes accounts for 5 to 10% of all diagnosed cases of the disease. Formerly called juvenile-onset or insulin-dependent diabetes, type 1 diabetes develops when the body’s immune system destroys pancreatic beta cells, the only cells in the body that make the hormone insulin that regulates blood glucose. Type 1 diabetes usually arises in children and young adults but can occur at any age. Management involves keeping blood glucose levels as close to normal as possible with three or more insulin injections a day or treatment with an insulin pump, careful monitoring of glucose, and close attention to diet and exercise.


Type 2 diabetes, or adult-onset diabetes, accounts for about 90 to 95% of all diabetes diagnosed in adults. It usually begins as insulin resistance, a disorder in which the cells do not use insulin properly. As the need for insulin rises, the pancreas gradually loses its ability to produce it. Type 2 diabetes is associated with older age, obesity, family history of diabetes, history of gestational diabetes, impaired glucose metabolism, physical inactivity, and race/ethnicity. African-Americans, Hispanic/Latino-Americans, American Indians, and some Asian-Americans and Native Hawaiians or other Pacific Islanders are at particularly high risk for type 2 diabetes and its complications.


Chronic kidney disease can lead to kidney failure, also called end-stage renal disease, requiring dialysis or a kidney transplant for survival. Chronic kidney disease affects more than 10% of Americans over age 20 and 35% of those over age 20 with diabetes. People with diabetes and chronic kidney disease account for 26.1%, or $18 billion, of Medicare costs for diabetes. Diabetes is the leading cause of kidney failure, accounting for nearly 38% (215,000) of Americans on dialysis or living with a kidney transplant. Each year 110,000 patients in the United States start treatment for kidney failure. These lifesaving treatments cost $42.5 billion annually.


According to an article published online in the New England Journal of Medicine (12 November 2011), controlling blood glucose early in the course of type 1 diabetes yields huge dividends, preserving kidney function for decades. Compared to conventional therapy, near-normal control of blood glucose beginning soon after diagnosis of type 1 diabetes and continuing an average six and a half years reduced by half the long-term risk of developing kidney disease, according to the Diabetes Control and Complications Trial (DCCT) and Epidemiology of Diabetes Interventions and Complications (EDIC) Research Group. The risk of kidney failure was also halved, but the difference was not statistically significant, perhaps due to the relatively small total number of patients who reached that stage of the disease.


The DCCT, conducted from 1983 to 1993 in 1,441 people with type 1 diabetes, found that intensive glucose control was superior to conventional control in delaying or preventing complications overall. EDIC continues to follow 1,375 DCCT participants to determine the long-term effects of the therapies beyond the initial treatment period.


The DCCT compared intensive to conventional control of blood glucose in people with type 1 diabetes. At the time, conventional treatment was one or two insulin injections a day with daily urine or blood glucose testing. Participants randomly assigned to intensive treatment were asked to keep glucose levels as near normal as possible. That meant trying to keep hemoglobin A1c (A1C) readings at 6% or less with at least three insulin injections a day or an insulin pump, guided by frequent self-monitoring of blood glucose. (A1C reflects average blood glucose over the previous two to three months.)


Participants entered the DCCT on average six years after onset of diabetes when complications of diabetes were absent or very mild. Half aimed for near-normal glucose control (intensive therapy) and the others received what was then standard glucose control. After an average 22-year follow-up, 24 in the intensive group developed significantly reduced kidney function and 8 progressed to kidney failure requiring dialysis or transplantation. On conventional therapy, 46 developed kidney disease, with kidney failure in 16.

Is 90 the new 85 or 80; 70 the new 60; and 50 the new 40? etc etc etc



In 1980, there were 720,000 people aged 90 and older in the United States. In 2010, there were 1.9 million people aged 90 and older. By 2050, the ranks of people 90 and older may reach 9 million, according to a report from the U.S. Census Bureau. The report describes this rapidly growing segment of the population which suggests that the designation of oldest-old should be changed from 85 to 90 years. The report, 90+ in the United States: 2006-2008, details the demographic, health and economic status of America’s oldest adults.


Based on the American Community Survey, the 27-page report describes in detail this rapidly growing population and states that a majority of the 90-plus population are widowed white women who live alone or in a nursing home. Most of them are high school graduates. Social Security provides almost half of their personal income, and almost all of them have health insurance coverage through Medicare and/or Medicaid. The vast majority say they have one or more types of disability.


The report says:


— An average person who has lived to 90 years of age has a life expectancy today of 4.6 more years (versus 3.2 years in 1929-1931), while those who pass the century mark are projected to live another 2.3 years.


–The majority (84.7%) of those 90 years and older reported having one or more limitations in physical function. Some 66% had difficulty in mobility-related activities such as walking or climbing stairs.


–An older person’s likelihood of living in a nursing home increases sharply with age. About 1% of what are called the young elderly (aged 65-69) live in a nursing home. The proportion rises to 3% for ages 75-79, 11.2% for ages 85-89, 19.8% at ages 90-94, 31.0% at ages 95-99 and up to 38.2% among centenarians.


–Women aged 90 years and older outnumber men nearly 3 to 1; 74.1% of the total population aged 90 and older in 2006-2008 were women.


–Whites represent 88.1% of the total 90-and-older population. Blacks make up 7.6%, Hispanics 4% and Asians 2.2%.


–The annual median income for people 90 and older was $14,760. Men had a higher income than women: $20,133 vs. $13,580. Social Security represents 47.9% of total personal income.

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



FDA Commissioner Announces Avastin Decision




On November 18, FDA Commissioner Margaret A. Hamburg, M.D., said that the FDA is revoking the approval of the breast cancer indication for Avastin (bevacizumab), after concluding that the drug has not been shown to be safe and effective for that use. Avastin will still remain on the market as an approved treatment for certain types of colon, lung, kidney and brain cancer (glioblastoma multiforme).


“This was a difficult decision. FDA recognizes how hard it is for patients and their families to cope with metastatic breast cancer and how great a need there is for more effective treatments. But patients must have confidence that the drugs they take are both safe and effective for their intended use,” Dr. Hamburg said. “After reviewing the available studies it is clear that women who take Avastin for metastatic breast cancer risk potentially life-threatening side effects without proof that the use of Avastin will provide a benefit, in terms of delay in tumor growth, that would justify those risks. Nor is there evidence that use of Avastin will either help them live longer or improve their quality of life.”


Avastin’s risks include severe high blood pressure; bleeding and hemorrhaging; heart attack or heart failure; and the development of perforations in different parts of the body such as the nose, stomach, and intestines.


FDA’s decision, outlined in Dr Hamburg’s 69-page opinion, involves Avastin used in combination with the cancer drug paclitaxel for those patients who have not been treated with chemotherapy for their form of metastatic breast cancer known as HER2 negative. This indication must now be removed from Avastin’s product labeling. FDA’s decision is based on an extensive record, which includes thousands of pages submitted to a public docket, data from several clinical trials and the record from a two-day hearing held in June, 2011.


Avastin was approved for metastatic breast cancer in February 2008 under the FDA’s accelerated approval program, which allows a drug to be approved based on data that are not sufficiently complete to permit full approval. The accelerated approval program provides earlier patient access to promising new drugs to treat serious or life-threatening conditions while confirmatory clinical trials are conducted. If the clinical trials do not justify the continued approval of the drug or a specific drug indication, the agency may revoke its approval. In this case, the accelerated approval was based on promising results from one study that suggested that the drug could provide a meaningful increase in the amount of time from when treatment is started until the tumor grows or the death of the patient.


After the accelerated approval of Avastin for breast cancer, the drug’s sponsor, Genentech, completed two additional clinical trials and submitted the data from those studies to the FDA. These data showed only a small effect on tumor growth without evidence that patients lived any longer or had a better quality of life compared to taking standard chemotherapy alone – not enough to outweigh the risk of taking the drug.


FDA’s Center for Drug Evaluation and Research, which is responsible for the approval of this drug, ultimately concluded that the results of these additional studies did not justify continued approval and notified Genentech it was proposing to withdraw approval of the indication.


Genentech did not agree with the Center’s evaluation of the data and, following the procedures set out in FDA regulations, requested a hearing on the Center’s withdrawal proposal, with a decision to be made by the Commissioner. That two-day hearing, which took place June 28-29, 2011, included recommendations from the FDA’s Oncologic Drugs Advisory Committee (ODAC), voting 6-0 in favor of withdrawing approval of Avastin’s breast cancer indication. After the hearing, the public docket remained open until Aug. 4, 2011. (In an earlier meeting of the ODAC, that committee had voted 12-1 in favor of the removal of the breast cancer indication from the Avastin label).


“FDA is committed to working with sponsors to bring promising cancer drugs to market as quickly as possible using tools like accelerated approval,” Dr. Hamburg said. “I encourage Genentech to consider additional studies to identify if there are select subgroups of women suffering from breast cancer who might benefit from this drug.”

Target Health (www.targethealth.com) a full service e*CRO, is committed to serve the pharmaceutical community through knowledge, experience, technology and connectivity. Target Health strives to optimize the life cycle of drugs, biologics and devices with expertise, leadership, innovation and teamwork. Target Health Inc. has fulltime staff dedicated to all aspects of Regulatory Affairs, Clinical Research, Biostatistics, Data Management, Strategic Planning and Drug and Device Development.



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