Science Weekly: What the brain can and can’t do

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We delve into the mysteries of the mind; plus, are we reaching the limits of what humans can understand?

Target e*CRF® Version 2

Target Health was honored to host our good friend and colleague, Dr. Jack Lee, President of LSK Global Pharma Services (LSK PS), our CRO partner in Korea. Prior to founding LSK PS, Dr. Lee spent 22 years at NIH and was chief of Biometry and Mathematical Statistics Branch at the National Institute of Child Health and Human Development.  LSK will be programming Target e*CRF Version 2.0 applications in Korea for the Asian markets. As a partner, Target Health will provide full support including training and hosting; and since we speak Korean, the partnership will be a win-win for each of our organizations. Target e*CRF Version 2.0 allows for our EDC partners to program data entry forms and edit checks

Target Health and LSK are already collaborating on an oncology program in collaboration with Big Pharma and a CRO in Australia, and LSK is using Target Document® for eTrial Master Files.  

For more information about Target Health contact Warren Pearlson (212-681-2100 ext 104). For additional information about software tools for paperless clinical trials, please also feel free to contact Dr. Jules T. Mitchel or Ms. Joyce Hays. Target Health’s software tools are designed to partner with both CROs and Sponsors. Please visit the Target Health Website, and if you like the weekly newsletter, ON TARGET, you’ll love the Blog.

First Implantable Artificial Kidney Prototype

A prototype uses kidney cells to help it perform vital functions.

Nearly 400,000 people in the US, and as many as two million worldwide, rely on dialysis machines to filter 1) ___ from their blood because of chronic kidney failure. Patients must be tethered to machines at least three times a week for three to five hours at a stretch. Even then, a 2) ___ machine is only about 13% as effective as a functional kidney, and the five-year survival rate of patients on dialysis is just 33-35%. To restore health, patients need a kidney 3) ___, and there just aren’t enough donor organs to go around. In August, there were 85,000 patients on the US waiting list, while only 17,000 kidney transplants took place last year.

A collaborative, multidisciplinary group is working to create the first implantable artificial kidney. The prototype, revealed last week, is compact, no larger than a soup can. It not only filters toxins out of the 4) ___ but also uses human kidney cells to perform other vital functions, such as regulating blood pressure and producing vitamin D. “Dialysis is not only time-consuming, but it’s also debilitating. Many patients don’t feel good, because it’s not doing all the functions of a normal, healthy kidney,” says bioengineer Shuvo Roy, whose lab at the University of California, San Francisco produced the new device and is already testing it in animals.

Making an artificial kidney small enough to fit inside the body is, however, a big challenge. A healthy kidney filters 90 liters of 5) ___ each day. Current dialysis machines are the size of a small refrigerator, and require substantial pressure to pump enough water through the machine’s porous membranes to allow contaminants to be filtered out of the blood. The new implant is a fusion of multiple lines of research, and takes advantage of two recent advances in the field. University of Michigan nephrologist David Humes has shown that human kidney cells could be used in a room-sized filtration machine to greatly improve the health of patients whose kidneys have stopped functioning, and Shuvo Roy and William Fissell MD, a 6) ___ at the Cleveland Clinic, have produced a nano-pore silicon membrane with a dense and precise pore-structure that could help miniaturize dialysis machines.

The prototype is a two-part system: half consists of a toxin-removing filter, in which thousands of silicon membranes are stacked together. Their nano-pores are so dense, and so precisely shaped, that they can filter very precisely using only the force of the body’s own blood 7) ___. Blood flows in through this filter, where the toxins, sugars, water, and salts are removed as a filtered solution. The clean blood and watery filtrate are both shunted into the other half of the system: a separate cartridge. Here, they flow over more silicon membranes coated with a single type of human kidney cell, which helps the device reabsorb some of the water, sugars, and salts, as well as produce vitamin D and help prevent blood pressure from sinking too low. These normal 8) ___ functions are not offered by traditional dialysis. The waste that’s not reabsorbed is shunted to a tube attached to the bladder and removed as waste in the urine just like a normal kidney would do.

It’s far from a complete system, and the researchers note that they don’t ever expect it to replace kidney transplants. “Your kidney has 20 to 30 cell types in it, all of which accomplish different functions. But we’d like to overcome a critical issue that’s emerged in renal failure,” says Fissell. “If you’re listed for a kidney 9) ___, you’re far more likely to die on the waitlist than you are to get a kidney.” He says the device could act as a bridge for patients awaiting transplant.

ANSWERS: 1) toxins; 2) dialysis; 3) transplant; 4) bloodstream; 5) water; 6) nephrologist; 7) pressure; 8) kidney; 9) transplant

Dr. Frances Kathleen Oldham Kelsey (1914 to Present)

Dr. Frances Oldham Kelsey is honored by the F.D.A.
Photo: Brendan Smialowski for The New York Times

RECOGNITION President Kennedy gave Dr. Kelsey the Distinguished Civilian Service Medal in August 1962 for saving newborns from the perils of the drug thalidomide.

Dr. Frances Oldham Kelsey is 96 now, nearly deaf and barely mobile. And though her story is nearly forgotten, she was once America’s most admired civil servant – celebrated for her dual role in saving thousands of newborns from the perils of the drug thalidomide and in serving as midwife to modern pharmaceutical regulation. Last Wednesday, Dr. Margaret Hamburg, FDA commissioner, honored Dr. Kelsey with the first Kelsey award. The award will come 50 years after Dr. Kelsey, then a new medical officer at the agency, first sat down to consider an application from the William S. Merrell Company of Cincinnati to sell a sedative named Kevadon, which was widely prescribed in Europe for morning sickness in pregnancy.

As it turned out, the drug (better known by its generic name, thalidomide) would cause thousands of children in Europe to be born limbless or with flipperlike arms and legs. With her probing analysis of Merrell’s application and her insistence on scientific rigor, Dr. Kelsey ensured that the effects in the US were far more limited. The thalidomide disaster led Congress to pass legislation giving the FDA authority to demand that drug makers prove their products safe and effective. Moreover, Dr. Kelsey helped write the rules that now govern nearly every clinical trial in the industrialized world, and was the first official to oversee them.

Dr. Kelsey might never have reached the FDA in the first place if her first name hadn’t sounded like a man’s. Born in 1914 in British Columbia, Frances Kathleen Oldham was sent to a private boys’ school because her parents expected her to become as educated as her older brother. She was hired sight unseen by Dr. Eugene Geiling, a renowned pharmacology professor at the University of Chicago, because he read her name as Francis. When she got the acceptance letter, in 1936, she realized his mistake and asked a professor at McGill University whether she could accept the job. “When a woman took a job in those days, she was made to feel as if she was depriving a man of the ability to support his wife and child,” Dr. Kelsey said in an interview at her home. “But my professor said: “Don’t be stupid. Accept the job, sign your name and put “Miss” in brackets afterward.”

She was soon put to work helping Dr. Geiling establish the toxicity of elixir of sulfanilamide, a medicine that would be linked with scores of deaths because it contained a deadly industrial solvent. The scandal led Congress to strengthen drug regulations, giving her a role in two of the three seminal events in FDA’s history.

She arrived at the FDA in 1960 as part of a new cadre of scientists who had begun insisting that drugs show clear evidence of effectiveness as a condition for approval, even though Congress had yet to grant the agency explicit authority to enforce that. Drugs could be sold 60 days after their makers filed information with the agency as long as it did not object; companies routinely sent new remedies to doctors and asked them to try the medicine in patients. Such testing was uncontrolled and entirely anecdotal.

Dr. Kelsey demanded better tests for thalidomide. She soon discovered that Kevadon had been linked in Europe with reports of nerve damage – reports the company had failed to provide her. “I had the feeling throughout the day,” she wrote after a meeting with company executives, “that they were at no time being wholly frank with me and that this attitude has obtained in all our conferences, etc., regarding this drug.” Company officials complained about Dr. Kelsey to her superiors, who supported her. When evidence became irrefutable that Kevadon caused horrendous birth defects, the company quietly withdrew its application.

Merrell executives had been insisting that “I was depriving people of this thing,” she said in the recent interview. “And then when it happened, I was so relieved to get them off my back. Amazing.” Dr. Kelsey’s role in the saga would have remained little known if not for a front-page article in The Washington Post – which, in turn, led to legislation giving the FDA far more power over the drug industry. President John F. Kennedy gave Dr. Kelsey the Distinguished Civilian Service Medal, and a picture of her accepting the award wearing a black dress, holding a white purse and looking demure but competent became the iconic image of the agency.

With the FDA given far more power, Dr. Kelsey set about with others at the agency to write rules for medical testing that created three distinct phases for human trials and strengthened rules for human protections and conflicts of interest. These rules have since been adopted worldwide. As the historian Dr. Carpenter put it: “She and the FDA had a huge role in determining the terms and sequence of what is now modern clinical science.” Source: The New York Times, September 2010, by Gardiner Harris  

Effect of Aspirin and NSAIDs on Risk and Survival From Colorectal Cancer

 

Previous studies have shown that aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) lower colorectal cancer (CRC) risk. However, the lowest effective NSAID dose, treatment duration, and effects on survival are not defined. In a large population-based case-control study, published online in Gut (15 September 2010) explored the relationship between NSAID dose and duration, CRC risk and overall CRC-specific survival.

The relationship between NSAID use and CRC risk was examined in 2279 cases and 2907 controls. Subjects completed food-frequency and lifestyle questionnaires. NSAID categories were low-dose aspirin (75 mg), non-aspirin NSAIDs (NA-NSAIDs) and any NSAID. Users were defined as taking >4 tablets/week for >1 month.

In all, 354 cases were taking low-dose aspirin compared to 526 controls. Low-dose aspirin use was associated with decreased CRC risk (OR 0.78; p=0.004), evident after 1 year and increasing with duration of use (p=0.004). NA-NSAID and any NSAID use were also inversely associated with CRC. However, here was no demonstrable effect of NSAIDS on all-cause (HR 1.11, p=0.22) or CRC-specific survival (HR 1.01, p=0.93).

According to the authors, his is the first study to demonstrate a protective effect against CRC associated with the lowest dose of aspirin (75 mg per day) after only 5 years use in the general population. NSAID use prior to CRC diagnosis does not influence survival from the disease.

Screening For Prostate Cancer: Systematic Review And Meta-Analysis Of Randomized Controlled Trials

According to an article published in the British Medical Journal (2010; 341:c4543), a study was performed to examine the evidence on the benefits and harms of screening for prostate cancer. The methodology used was a systematic review and meta-analysis of randomized controlled trials identified in electronic databases including Medline, Embase, CENTRAL, abstract proceedings, and reference lists up to July 2010.

The review methods Included studies were randomized controlled trials comparing screening by prostate specific antigen with or without digital rectal examination versus no screening. Data abstraction and assessment of methodological quality with the GRADE approach was assessed by two independent reviewers and verified by the primary investigator. Mantel-Haenszel and inverse variance estimates were calculated and pooled under a random effects model expressing data as relative risks and 95% confidence intervals.

Six randomized controlled trials with a total of 387,286 participants that met inclusion criteria were analyzed. Results showed that screening was associated with an increased probability of receiving a diagnosis of prostate cancer (relative risk 1.46; P<0.001) and stage I prostate cancer (1.95; P=0.005). However, there was no significant effect of screening on death from prostate cancer (0.88; P=0.25) or overall mortality (0.99; P=0.44). All trials had one or more substantial methodological limitations. None provided data on the effects of screening on participants’ quality of life. Little information was provided about potential harms associated with screening.

According to the authors, the existing evidence from randomized controlled trials does not support the routine use of screening for prostate cancer with prostate specific antigen with or without digital rectal examination.

Combined Impact of Lifestyle-Related Factors on Total and Cause-Specific Mortality among Chinese Women

Although cigarette smoking, excessive alcohol drinking, obesity, and several other well-studied unhealthy lifestyle-related factors each have been linked to the risk of multiple chronic diseases and premature death, little is known about the combined impact on mortality outcomes, in particular among Chinese and other non-Western populations. As a result, a study published in PLoS Medicine (2010;7:e1000339), was performed to quantify the overall impact of lifestyle-related factors beyond that of active cigarette smoking and alcohol consumption on all-cause and cause-specific mortality in Chinese women.

Data were used from the Shanghai Women’s Health Study, an ongoing population-based prospective cohort study in China. Participants included 71,243 women aged 40 to 70 years enrolled during 1996-2000 who never smoked or drank alcohol regularly. A healthy lifestyle score was created on the basis of five lifestyle-related factors shown to be independently associated with mortality outcomes (normal weight, lower waist-hip ratio, daily exercise, never exposed to spouse’s smoking, higher daily fruit and vegetable intake). The score ranged from zero (least healthy) to five (most healthy) points.

During an average follow-up of 9 years, 2,860 deaths occurred, including 775 from cardiovascular disease (CVD) and 1,351 from cancer. Adjusted hazard ratios for mortality decreased progressively with an increasing number of healthy lifestyle factors. Compared to women with a score of zero, hazard ratios for women with four to five factors were 0.57 for total mortality, 0.29 for CVD mortality, and 0.76 for cancer mortality. The inverse association between the healthy lifestyle score and mortality was seen consistently regardless of chronic disease status at baseline. The population attributable risks for not having 4-5 healthy lifestyle factors were 33% for total deaths, 59% for CVD deaths, and 19% for cancer deaths.

According to the authors, this is the first study to quantify the combined impact of lifestyle-related factors on mortality outcomes in Chinese women, a healthier lifestyle pattern – including being of normal weight, lower central adiposity, participation in physical activity, nonexposure to spousal smoking, and higher fruit and vegetable intake – was associated with reductions in total and cause-specific mortality among lifetime nonsmoking and nondrinking women. The authors added that this supports the importance of overall lifestyle modification in disease prevention.

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FDA Approves Devices for Heart Failure Patients

The FDA has approved a new indication for three cardiac resynchronization therapy defibrillators (CRT-D) used to treat certain heart failure patients. The new use is for patients with an abnormality known as left bundle branch block, which occurs when there is delayed activation and contraction of the left ventricle. The three devices, all manufactured by Boston Scientific Corp., are intended to treat patients with left bundle branch block who have either mild heart failure or heart failure with no apparent symptoms.

The CRT-D device combines two functions. As an implantable cardioverter defibrillator (ICD) it senses dangerous abnormal heart rhythms and then attempts to shock the heart back into a normal rhythm. As cardiac resynchronization therapy, it generates small electrical impulses to coordinate the beating of the left and right ventricles so that they work together more effectively to pump blood throughout the body.

CRT-Ds are to be used as an addition to, not a replacement for, heart failure drug therapy.

The FDA based its approval on the results of the 1,820-patient Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy (MADIT-CRT) clinical study. The study which followed 1,820 patients for an average of nearly three years at 110 centers in the United States, Europe, Canada, and Israel. It compared CRT-D therapy to ICD-only therapy in specific heart failure patients to determine whether it reduced the risk of death and heart failure. In patients with left bundle branch block, who represented 70% of the study group, CRT-D showed a reduction in the risk of death and heart failure by 57%, as compared to ICD alone.

The rate of complications was considered to be acceptable by the FDA for this device, however, physicians should adequately inform patients about potential complications.

As a condition of FDA approval, Boston Scientific must conduct two post-approval studies. One study will evaluate complications and long-term mortality benefits of CRT-D in patients with left bundle branch block identified through the National Cardiovascular Data Registry. The other will follow patients from the original MADIT-CRT clinical study every six months for five years to assess long-term mortality benefits of CRT-D vs. ICD.

For more information about our expertise in Medical Affairs, contact Dr. Mark Horn. For Regulatory Affairs, please contact Dr. Jules T. Mitchel or Dr. Glen Park.