Clinical Trial Transformation Initiative (CTTI)

Target Health has been a member of the Steering Committee of Clinical Trial Transformation Initiative (CTTI) beginning in 2008. The mission of CTTI is “To identify practices that through broad adoption will increase the quality and efficiency of clinical trials.” Currently, over 50 organizations comprise CTTI, including government agencies (the FDA, Centers for Medicare and Medicaid Services (CMS), Office of Human Research Protections (OHRP), National Institutes of Health (NIH), and other national and international governmental bodies), industry representatives (pharmaceutical, biotech, device, and CROs), patient and consumer representatives, professional societies, investigator groups, academic institutions, and other interested parties. One of the projects CTTI has championed is the monitoring of clinical trials. A poster was presented at the 2010 Annual Meeting of the Society of Clinical Trials entitled “A CTTI Survey of Current Monitoring Practices.” A manuscript will be published shortly. Let us know if your company would be interested in joining. It is a stellar group of people.

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 at:

www.targethealth.com

Genetic Signatures of Human Exceptional Longevity Discovered

Still raring to go, Montana resident Walter Breuning turned 113 in September. Just one in 6,000 people lives to be 100, and one in 7 million makes it past 110.   John Moore, Getty Images

While environment and family history are factors in healthy aging, genetic variants play a critical and complex role in conferring exceptional 1) ___. In a study released July 1 online by the journal Science, a group of genetic variants were identified that can predict exceptional longevity in humans with 77% accuracy — a breakthrough in understanding the role of 2) ___ in determining human lifespan. Based upon the hypothesis that exceptionally old individuals are carriers of multiple genetic variants that influence their remarkable survival, a genome-wide association study of 3) ___ was conducted. Centenarians are a model of healthy aging, as the onset of disability in these individuals is generally delayed until they are well into their mid-nineties. Researchers built a unique genetic model that includes 150 genetic variants, known as single nucleotide polymorphisms or 4) ___. They found that these 150 variants could be used to predict if a person survived to very old ages (late 90s and older) with a high rate of accuracy. In addition, the team’s analysis identified 19 genetic 5) ___ or “genetic signatures” of exceptional longevity that characterized 90% of the centenarians studied. The different signatures correlated with differences in the prevalence and age-of-onset of diseases such as dementia and hypertension, and may help identify key subgroups of healthy aging. Notably, the team found that 45% of the oldest centenarians — those 110 years and older — had a 6) ___ signature with the highest proportion of longevity-associated genetic variants. These genetic signatures are a new advance towards personalized genomics and predictive medicine, where this analytic method may prove to be generally useful in prevention and screening of numerous 7) ___, as well as the tailored uses of medications. The researchers developed a novel Bayesian statistical approach to analyze 8) ___ data from more than 1,000 centenarians and several control groups, and to identify those SNPs that were most predictive of being centenarians or controls. The team began by using the SNPs that were most likely associated with exceptional longevity, and once the researchers identified 150 SNPs, they found that adding more variants did not further improve the ability to predict whether a person was a centenarian or a control subject. The methodology that the scientists developed can be applied to other complex genetic traits, including 9) ___ disease, Parkinson’s, cardiovascular disease and diabetes. Besides looking at which genetic variants were associated with longevity, the authors looked into whether the absence of disease-associated variants also played an important role. They did this by analyzing how many disease-associated 10) ___ each centenarian had, compared to each of the controls. Their analysis found little difference between the two groups, suggesting that the presence of genetic variants associated with longevity is of more importance than the absence of disease-associated variants. If these findings are confirmed, they would suggest that predicting disease risk using disease-associated variants may be 11) ___ and potentially misleading, without more information about other genetic variants that could attenuate such risk. Overall, the preliminary data suggest that exceptional longevity may be the result of an enrichment of longevity-associated variants that counter the effect of disease-associated variants and contribute to the compression of morbidity and/or disability towards the end of these very long lives. The researchers noted that the 77% accuracy rate of predictions shows that genetic data can indeed predict exceptional longevity without knowledge of any other risk factor. However, the authors added that this prediction is not perfect, however, and although it may improve with better knowledge of the variations in the human genome, its limitations confirm that environmental factors (e.g., lifestyle) also contribute in important ways to the ability of humans to survive to very old ages. They cautioned that they developed this genetic risk model as a way to dissect the complex genetic bases of exceptional longevity and to discover the different genetic paths to age 100 and older. An understanding of the implications of this model’s use in the general population would be necessary before this test is marketed. This is a novel approach to studying genetic contributions to exceptional longevity. It adds to a growing set of analytical tools that aim to identify and understand the complex genetic and 12) ___ factors that lead to healthy long life.   Source: Boston University Medical Center

ANSWERS: 1) longevity; 2) genes; 3) centenarians; 4) SNPs; 5) clusters; 6) genetic; 7) diseases; 8) genotype; 9) Alzheimer’s; 10) variants; 11) inaccurate; 12) environmental

U.S. Malaria Deaths, 1870

 

While malaria still kills over 1 million people each year, most of those deaths occur in sub-Saharan Africa—the United States has been free of the disease since 1951. In the 19th century, however, malaria was extremely common within the United States, with over 1 million cases reported during the Civil War alone. The map below depicts deaths from malaria in 1870—10 years before the malaria parasite was even discovered.

#1 – Believed to have been brought to the Americas by Europeans in the late 1600s, malaria primarily impacted those in the Southeast and port cities, but extended as far north as the Dakotas, says Margaret Humphreys, a history of medicine professor at Duke University.

#2 – Of the five species of the Plasmodium parasite that can cause malaria, P. falciparum and P. vivax were the most common in the United States. “The malaria that is shown here north of the Mason-Dixon Line was likely vivax malaria,” Humphreys says, which “can hide out in the liver and re-emerge later, causing relapses.”

#3 – During the Civil War, the presence of malaria in the United States skyrocketed, killing some 10,000 Union soldiers annually during the war. The war brought “hordes of men into the swampy areas of the coastal south and along the major rivers”—such as the Mississippi, James, and Potomac—”who then took the parasite home with them,” says Humphreys.

#4 – In 1946, the Communicable Disease Center (today’s Centers for Disease Control and Prevention, CDC) was created in Atlanta, Georgia, with the primary focus of eliminating malaria from the South. Through a variety of efforts, including draining swamps, removing mosquito breeding sites, and spraying pesticides, malaria was considered eradicated from the United States within just 5 years.

Source: The-Scientist.com

Aiming for Near-Normal Blood Sugar Did Not Delay Combined Risk of Diabetic Damage but Some Signs of Damage to Kidneys, Eyes, Nerves Delayed

 

About 24 million people in the US have diabetes. It is the main cause of kidney failure, limb amputations, and new onset blindness in adults and a major cause of heart disease and stroke. Type 2 diabetes, which accounts for up to 95% of all diabetes cases, becomes more common with increasing age. It is strongly associated with obesity, physical inactivity, family history of diabetes, history of gestational diabetes (diabetes that occurs during pregnancy), and impaired glucose metabolism, and it is more common in minority groups. The prevalence of diagnosed diabetes has more than doubled in the last 30 years, due in large part to the upsurge in obesity and aging of the population. Over time, diabetes damages the small blood vessels of the eyes, nerves, kidneys and other organs, leading to pain and disability. Heart disease due to damaged large blood vessels is a major cause of death in persons with type 2 diabetes. The longer a person has diabetes, the greater the chances of serious complications, including vision loss and blindness, foot ulcers and amputations, kidney disease and kidney failure, and heart disease and stroke. According to an article which appeared online in The Lancet (29 June 2010), in people with longstanding type 2 diabetes who are at high risk for heart attack and stroke, lowering blood sugar to near-normal levels did not delay the combined risk of diabetic damage to kidneys, eyes, or nerves, but did delay several other signs of diabetic damage. These findings are from the NIH-funded Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. The ACCORD clinical study compared the effect of intensive control of blood sugar, blood pressure, and blood lipids to standard, less-intensive treatments on the risk of major cardiovascular events in more than 10,000 adults with established type 2 diabetes. The study’s intensive glycemia arm was halted in February 2008 due to excess deaths in that group. At that time, participants in the intensively treated group were moved to standard glucose control. At enrollment, ACCORD participants averaged 62 years of age and were obese. In addition to having type 2 diabetes for an average of 10 years, about one-third had pre-existing heart disease, and the remainder had at least two additional cardiovascular disease risk factors. They also had high blood sugar, as measured by the hemoglobin A1C test, which shows average blood sugar in the preceding two to three months. Half of participants had an A1C over 8.1%- above the currently recommended target for good control. A1C values in people without diabetes are less than 6%. Previously reported results showed that over about three-and-a-half years of follow up, participants in the intensive blood sugar group had a 22% higher risk of death (5% versus 4%) and a three times higher risk of seriously low blood sugar (10.5% versus 3.5%) compared with participants in the standard blood sugar control group. A secondary goal of the ACCORD blood sugar trial was to determine the effects of near-normal glucose control compared with standard control on microvascular, or small blood vessel, damage to organs and tissues. Earlier, well conducted clinical trials in patients with newly diagnosed type 1 and type 2 diabetes had proven lowering blood sugar levels reduced eye, nerve and kidney disease. In ACCORD, the A1C target for the intensively treated group was less than 6%, a level seen in adults without diabetes and significantly lower than the levels tested in earlier trials. The goal for standard control was an A1C of 7 to 7.9%, an average range achieved by individuals treated for type 2 diabetes in the US. Both groups were treated with FDA-approved diabetes medications. Eye, nerve, and kidney complications in the two groups were compared after 3.7 years, when intensive control was halted, and again at the study’s end after 5 years. When intensive glucose treatment was halted in the group receiving such treatment, half those participants had an A1C of 6.4% or lower, which rose to 7.2% at study end. In the standard treatment group, that A1C measure was 7.5%, rising to 7.6% by the end of the study. The treatment groups did not differ in the rate of progression to kidney failure, major vision loss, or advanced peripheral neuropathy, a common nerve problem in diabetes that usually begins as tingling or numbness in the feet. However, people in intensive control had less deterioration in a vision test, and 20% fewer cataract surgeries compared with those in standard control. They also had a 30% lower rate of protein leakage in the urine, a sign of kidney disease and increased risk of heart disease. Testing for vibratory sensation, an indicator of nerve health, showed no difference between the groups, but the intensively controlled group scored better on other nerve tests. The effects of intensive blood sugar control on vision are consistent with findings from the ACCORD Eye Study, which explored the effects of intensive treatments on progression of diabetic retinopathy in a subset of about 3,000 ACCORD participants. The most common cause of vision loss in working-age Americans, diabetic retinopathy is a disease in which blood vessels in the eye’s light-sensitive retinal tissue are damaged by diabetes. Intensive blood sugar control was found to be beneficial in retarding the progression of diabetic retinopathy.

Does Pregnancy Provide Vaccine-Like Protection Against Rheumatoid Arthritis?

Previous studies have evaluated the correlation between rheumatoid arthritis (RA) risk and pregnancy history, with conflicting results. As a result, a study published in Arthritis & Rheumatism (2010;62:1842-1848), was performed to examine the effect of parity (number of live births) on RA risk. The study examined parity and RA risk using results from a population-based prospective study in Seattle, Washington and the surrounding area and compared women who were recently diagnosed as having RA (n = 310) with controls (n = 1,418). The study also evaluated the distribution of parity in cases according to Human Leucocyte Antigen (HLA) genotype. HLA are a group of antigens present on the surface of nucleated body cells that are coded for by the major histocompatibility complex of humans and thus allow the immune system to distinguish self and nonself. Results showed a significant reduction of RA risk associated with parity (relative risk [RR] 0.61; P = 0.005). RA risk reduction in parous women was strongest among those who were younger. Most striking was that RA risk reduction correlated with the time that had elapsed since the last time a woman had given birth. RA risk was lowest among women whose last birth occurred 1-5 years previously (RR 0.29), with risk reduction lessening progressively as the time since the last birth increased (for those 5-15 years since last birth, RR 0.51; for those >15 years, RR 0.76), compared with nulliparous (no live birth) women (P for trend = 0.007). No correlation was observed between RA risk and either age at the time a woman first gave birth or a woman’s total number of births. Among cases with the highest genetic risk of RA (i.e., those with 2 copies of RA-associated HLA alleles), a significant underrepresentation of parous women versus nulliparous women was observed (P = 0.02). According to the authors, in the present study, there was a significantly lower risk of RA in parous women that was strongly correlated with the time elapsed since a woman had last given birth. While the explanation for the findings is not known, HLA-disparate fetal microchimerism can persist many years after a birth and could confer temporary protection against RA.

Gestational Age at Delivery and Special Educational Need

 

Previous studies have demonstrated an association between preterm delivery and increased risk of special educational need (SEN). As a result, a study published in PLoS Medicine (8 June 2010) was performed to examine the risk of SEN across the full range of gestation. The investigation was a population-based, retrospective study by linking school census data on the 407,503 eligible school-aged children resident in 19 Scottish Local Authority areas (total population 3.8 million) to their routine birth data. SEN was recorded in 17,784 (4.9%) children; 1,565 (8.4%) of those born preterm and 16,219 (4.7%) of those born at term. Results showed that the risk of SEN increased across the whole range of gestation from 40 to 24 weeks: 37-39 wk adjusted odds ratio (OR) 1.16; 33-36 wk adjusted OR 1.53; 28-32 wk adjusted OR 2.66 and; 24-27 wk adjusted OR 6.92. There was no interaction between elective versus spontaneous delivery. Overall, gestation at delivery accounted for 10% of the adjusted population attributable fraction of SEN. Because of their high frequency, early term deliveries (37-39 wk) accounted for 5.5% of cases of SEN compared with preterm deliveries (<37 wk), which accounted for only 3.6% of cases. According to the authors, gestation at delivery had a strong, dose-dependent relationship with SEN that was apparent across the whole range of gestation. However, the authors added that since early term delivery is more common than preterm delivery, the former accounts for a higher percentage of SEN cases and that the findings have important implications for clinical practice in relation to the timing of elective delivery.

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

 

CDER Drug Shortage Program (DSP)

The Drug Shortage Program (DSP), within the Center for Drug Evaluation and Research (CDER), was established to address potential or actual shortages of prescription, over-the-counter, or generic drugs that have a significant impact on public health. Through communication, facilitation and negotiation, DSP works with pharmaceutical manufacturers, review divisions, compliance and other components of FDA to manage product shortages. The DSP focuses on shortages of medically necessary products since these shortages have the greatest impact on public health. The Drug Shortage page on the FDA website lists shortages primarily of medically necessary products. Shortages that are expected to be resolved quickly or which involve only a particular strength or package size, which has a substitute strength(s) and package size(s), are not usually the focuses of the DSP. Over the last ten years, the number of shortages has continued to increase. There are many reasons for this increase in shortages and some of the causes are as follows:

  1. Manufacturing issues – this may include problems with manufacturing, enforcement activities, raw material shortages, packaging shortages, and other reasons
  2. Business decisions may be made by firms to discontinue manufacturing of a drug – newer products continue to replace older products due to better safety profiles, better efficacy, more convenient dosing regimens, etc.
  3. Limited manufacturing capacity – often multiple products are produced on the same equipment which means that an increase in production of one product will usually result in a delay for another product produced on the same production line
  4. Market concentration – as firms discontinue manufacturing of various products, only one or two firms may remain as producers of a product.

 

Once a drug is determined to be in shortage the DSP consults with the CDER review division that has medical expertise on the drug in shortage to determine whether the drug is a medically necessary drug product. (A medically necessary drug is defined as a product used to prevent or treat a serious or life-threatening disease or medical condition for which there is no other available source of that product, alternative drug or therapy available.) On occasion expertise from outside the FDA is also obtained to make such a determination. The approved and unapproved (“off-label”) uses of a product are taken into consideration. There are many shortage situations over which FDA has no regulatory authority. FDA may, however, do the following:

  1. Expedite review of submissions from manufacturers – these submissions may be in support of a marketing application for a new product (NDA or ANDA), or may be in support of manufacturing changes which will allow a product to be available (for example, a chemistry supplement for a new manufacturing site) or may involve other issues (for example, toxicity data for an impurity identified in a product)
  2. Identify alternate manufacturers that can initiate or ramp-up production
  3. Find new/additional sources of raw material
  4. Advise/consult with sponsors on resolution of manufacturing issues
  5. Allow temporary import of a non-US product, in rare instances

 

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.

Target Health (www.targethealth.com) is a full service eCRO with full-time staff dedicated to all aspects of drug and device development.

Areas of expertise include Regulatory Affairs, comprising, but not limited to, IND (eCTD), IDE, NDA (eCTD), BLA (eCTD), PMA (eCopy) and 510(k) submissions, execution of Clinical Trials, Project Management, Biostatistics and Data Management, EDC utilizing Target e*CRF®, and Medical Writing.

Target Health has developed a full suite of eClinical Trial software including:

1) Target e*CRF® (EDC plus randomization and batch edit checks)

2) Target e*CTMS™

3) Target Document®

4) Target Encoder®

5) Target Newsletter®

6) Target e*CTR™ (electronic medical record for clinical trials).

Target Health ‘s Pharmaceutical Advisory Dream Team assists companies in strategic planning from Discovery to Market Launch. Let us help you on your next project.

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