Science Weekly: The sun’s effect on climate change

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The effects of solar activity on global warming; a drug that heightens the female libido; and a song about evolution

Target Health Contribute to 4 Regulatory Approvals in 2009

Target Health is pleased to announce that Target e*CRF® has been used for all Phase 2 and Phase 3 studies for the following programs approved in 2009.  In addition, for 2 of the programs, Target Health provided full CRO services. 

  • FDA – ULESFIA (Head Lice) – Summers Laboratories, Inc./Sciele, USA – EDC; Monitoring; DM; Statistics; Writing; Toxicology; NDA (eCTD)
  • EMEA – ellaOne® (Emergency Contraception) HRA Pharma, France – EDC ; Monitoring; DM; Statistics; Writing
  • FDA/EMEA DEGARELIX – (Prostate Cancer) Ferring Pharmaceuticals, Denmark, USA – EDC
  • HEALTH CANADA – AUGMENTTM Bone Graft (Hindfoot and Ankle Fusion Surgery) Biomimetic Therapeutics, USA – EDC

For more information about Target Health and our software tools for paperless clinical trials, please contact Dr. Jules T. Mitchel (212-681-2100         212-681-2100 ext 0) 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

Saliva Proteins Change as Women Age

In a step toward using human saliva to tell whether those stiff joints, memory lapses, and other telltale signs of aging are normal or red flags for 1) ___, scientists are describing how the protein content of women’s saliva change with advancing age. The discovery could lead to a simple, 2) ___ test for better diagnosing and treating certain age-related diseases in women, they suggest in a report in the Journal of Proteome Research. These diseases include lupus, Sj?grens syndrome (associated with dry mouth and dry eye), and other immune-related disorders that affect millions of women worldwide, often at higher rates than in 3) ___.   Human 4) ___ contains many different proteins involved in digestion, disease fighting, and other functions. Scientists are seeking ways to use the proteins as molecular “fingerprints” to develop quick 5) ___ tests that provide an alternative to the needle sticks currently needed for blood tests. To do that, they need detailed information on how normal 6) ___ affects these proteins. The study analyzed saliva proteins in healthy women between the ages 20-30 and 55-65, and identified 293 proteins that differed between the two age groups. Most were involved in the immune system’s defenses against infection. Older women had almost twice as many immune-related 7) ___ than younger women. The results suggest that it is critical to take into consideration these normal differences in protein expression when searching for clinically relevant, disease specific biomarkers.

ANSWERS: 1) disease; 2) noninvasive; 3) men; 4) saliva; 5) diagnostic; 6) aging; 7) proteins

Gideon Mantell MD – Forward Bending Test for Scoliosis (1790-1852)

If anything, the 19th century English surgeon and paleontologist Gideon Mantell is known for his contributions to our understanding of dinosaurs. His most famous accomplishment was the description of Iguanodon, but Mantell has another legacy that is not as well-known. It was his last contribution to science. Like many other early paleontologists Mantell had to carve out his own career, and he studied fossils when not busy with his duties as a surgeon. As Mantell began to gain recognition for his work on fossils, his passion for paleontology became so consuming that it nearly bankrupted the family. As Mantell went about his work he often felt acute leg and back pain which he attributed to various causes. Maybe it was the long hours spent hunched over patients, his weight, or some other factor, but in the fall of 1841 things got a lot worse. On October 11, 1841 Mantell was forced to leap from his coach when the driver tangled the reins and crashed the carriage. Now Mantell was in even more pain than before, and towards the latter part of the month he was effectively paralyzed from the waist down. Even as he regained feeling in his legs, they would sometimes go numb when he leaned the wrong way or made too strenuous an effort. Mantell knew something was wrong with his back, but he was not sure what it was. By the fall of the following year a tumor-like swelling appeared on the side of Mantell’s spine. He suspected that it was some kind of abscess. The leading hypothesis was that Mantell’s vertebrae had become diseased, but they differed as to what method of treatment would heal the paleontologist. One recommended that a topical ointment might help while another advised that “gentle carriage exercise” and some “sarsaparilla” would be just the thing. This difference of opinion frustrated Mantell, but for a few years afterward the pain subsided enough to let him get on with his work. In 1849 the pain intensified but almost nothing could make it better. Mantell experimented with painkillers to try to soothe the injury, but this would ultimately prove to be his undoing. On November 11, 1852 Mantell took opium on an empty stomach and overdosed. He was 62 years old when he died. Given that Mantell’s poor condition was well known among academics an autopsy was performed by a Dr. Hodgkin and William Adams on November 11, 1852. What they found was that Mantell had been suffering from a severe case of scoliosis in his lumbar vertebrate (or those in the lower back above the pelvis). This part of Mantell’s backbone was distorted, yet the medical experts Mantell saw about his condition could not have seen this if they examined Mantell while he was standing up straight or lying down flat. The curvature of the spine only became visible when the back was bent forward, an observation that Adams would use to establish the forward-bending test to detect cases of scoliosis in living patients. After Adams and Hodgkin completed their examination they removed the diseased portion of Mantell’s spine for preservation in the Hunterian Museum. If you want to find Mantell’s bones today, though, you are out of luck. The portion of Mantell’s spine and the plaster cast made of his diseased bones were destroyed in 1969 citing “lack of space.” This was an unfortunate loss for historians of science and medical practitioners curious about the condition which led to the founding of the “Adams forward bend test”  This account was primarily derived from Fairbank, J.C.T. (2004) “William Adams and the spine of Gideon Algernon Mantell.” Annals of the Royal College of Surgeons of England. Vol 86, pp. 349-352.

Link Identified Between Preeclampsia and Reduced Thyroid Function

The thyroid gland, located in the front of the throat, makes hormones that help regulate heart rate, blood pressure, body temperature, and the conversion of food into energy. Reduced thyroid functioning, or hypothyroidism, results in overall weakness and fatigue and also increases the risk for cardiovascular disease. Preeclampsia is a life-threatening complication that occurs in 3 to 5% of pregnancies. The condition results in high blood pressure and protein in the urine. Preeclampsia may begin with mild symptoms. It can then progress to severe preeclampsia and to eclampsia – dangerously high blood pressure and convulsions – which may result in disability or death. The only cure for preeclampsia is delivery of the baby. The causes of preeclampsia are not known. In earlier work, it was reported that high levels of two molecules in the blood may cause symptoms of preeclampsia. (http://www.nichd.nih.gov/news/releases/preeclampsia_endoglin.cfm.) One of those molecules, soluble fms-like tyrosine kinase 1 (sFlt-1), acts by blocking a protein called vascular endothelial growth factor (VEGF). Previous studies have found that some cancer patients receiving treatments that block VEGF have developed hypothyroidism. As a result, a study published in the BMJ (2009;339:b4336), was performed to investigate whether women with preeclampsia might also experience similar problems with thyroid functioning. The analysis combined two separate studies which each suggested a link between preeclampsia and reduced thyroid function. In the first study, results showed that women who developed preeclampsia were more likely to have slightly reduced thyroid functioning during the last weeks of their pregnancies. The second study found that women who had preeclampsia during their pregnancies were more likely to have reduced thyroid functioning more than 20 years after they had given birth, when compared to women who had not had preeclampsia during pregnancy. The findings suggest that the possible development of hypothyroidism is a consideration in patients with a history of preeclampsia. For the current study, blood samples collected from an earlier NIH-led study on preeclampsia were tested for levels of thyroid stimulating hormone (TSH), which stimulates the thyroid gland.  Elevated levels of TSH are an indication that the thyroid is not functioning properly. Results showed that early in their pregnancies, women who went on to develop preeclampsia had thyroid functioning identical to that of the women who never developed preeclampsia. However, toward the end of their pregnancies, the women with preeclampsia had, on average, much higher levels of TSH than women with no history of preeclampsia.  Moreover, the increase in TSH was strongly associated with an increase in blood levels of sFLT-1. Although they did not have any other symptoms of reduced thyroid function, 1 out of every 4 of the other women with preeclampsia had levels of TSH above the range considered normal. Of the women without preeclampsia, that proportion was only 1 in 7. The first study did not provide information on whether reduced thyroid functioning extended beyond the end of the pregnancy, when preeclampsia’s symptoms cease. The researchers next turned to data collected in the mid-1990s in a county wide study in Norway. Data were analyzed from 7,121 women who had given birth to a first child in 1967 or later, and had had their blood samples tested for thyroid function in the county wide study. Results showed that the women who had preeclampsia in their first pregnancy were 1.7 times as likely to have high TSH as the women who had not had preeclampsia. Women who had preeclampsia in both their first and second pregnancies were nearly 6 times as likely to have high TSH levels.

Gene Mutations Underlying Risk for Most Common Form of Parkinson’s Disease

Parkinson’s disease (PD), which affects about 1.5 million Americans, is a progressive neurologic disorder caused by the degeneration of nerve cells in the portion of the brain that controls movement. The likelihood of developing the disorder increases with age and involves a combination of environmental risk factors and genetic susceptibility. According to an article published online in Nature Genetics (Nov. 15, 2009), it was found that two genes containing mutations known to cause rare familial forms of parkinsonism are also associated with the more common, sporadic form of the disease where there is no family history. The finding came in the largest genome-wide association study (GWAS) reported to date involving PD. GWAS studies look in the DNA on all of the chromosomes in a specific population of individuals for common genetic associations with a disease. To date, such studies have been done on relatively small numbers of samples and have not been able to identify genetic variations of smaller effect in PD. But now, GWAS studies in very large sample sets are able to identify these elusive genetic variations. Collaborating scientists in the United States and Europe pooled nearly 14,000 DNA samples and data to confirm that mutations in the alpha-synuclein (SNCA) gene and microtubule associated protein tau (MAPT), both present in the general population, are risk factors for sporadic PD. In an independent study from Japan, a different combination of genetic variants as risk factors was identified in people of Japanese descent, a finding that highlights the power of GWAS in comparing risk factors among different populations. The two-phase GWAS first analyzed DNA samples of 1,713 people with the disease and 3,978 free of the disorder, all of whom were Europeans. The findings were then replicated in a similar group of 3,361 people with PD and 4,573 without the disorder. Following the initial findings implicating SNCA and MAPT variants as risk factors for typical PD, the team then compared results with researchers performing a GWAS study in a group of Japanese people (2,816 with PD and 3,401 free of the disorder). This second GWAS also revealed the strong association for SNCA but not for MAPT. Additionally, both GWAS studies found evidence for two additional risk variants; the first, which was strongest in the Japanese population, was named Park16; the second is close to a gene, LRRK2, previously found to contain mutations that cause an inherited form of PD.

Cancer Incidence and Mortality After Treatment With Folic Acid and Vitamin B12

Recently, concern has been raised about the safety of folic acid, particularly in relation to cancer risk. As a result, a study published in the Journal of the American Medical Association (2009;302:2119-2126), was performed to evaluate effects of treatment with B vitamins on cancer outcomes and all-cause mortality. The study was a combined analysis and extended follow-up of participants from 2 randomized, double-blind, placebo-controlled clinical trials (Norwegian Vitamin Trial and Western Norway B Vitamin Intervention Trial). A total of 6,837 patients with ischemic heart disease were treated with B vitamins or placebo between 1998 and 2005, and were followed up through December 31, 2007. Treatments included oral treatment with 1) folic acid (0.8 mg/d) plus vitamin B12 (0.4 mg/d) and vitamin B6 (40 mg/d) (n = 1708); 2) folic acid (0.8 mg/d) plus vitamin B12 (0.4 mg/d) (n = 1703); 3) vitamin B6 alone (40 mg/d) (n = 1705); or placebo (n = 1721). The main outcome measures included 1) cancer incidence, 2) cancer mortality, and 3) all-cause mortality. Results showed that after a median 39 months of treatment and an additional 38 months of observational follow-up, 341 participants (10.0%) who received folic acid plus vitamin B12 vs. 288 participants (8.4%) who did not receive such treatment were diagnosed with cancer (hazard ratio [HR], 1.21; P = .02). A total of 136 (4.0%) who received folic acid plus vitamin B12 vs 100 (2.9%) who did not receive such treatment died from cancer (HR, 1.38; P = .01). A total of 548 patients (16.1%) who received folic acid plus vitamin B12 vs 473 (13.8%) who did not receive such treatment died from any cause (HR, 1.18; P = .01). Results were mainly driven by increased lung cancer incidence in participants who received folic acid plus vitamin B12. Vitamin B6 treatment was not associated with any significant effects. According to the authors, treatment with folic acid plus vitamin B12 was associated with increased cancer outcomes and all-cause mortality in Norwegian patients with ischemic heart disease, where there is no folic acid fortification of foods.

TARGET HEALTH excels in Regulatory Affairs and works closely with many of its clients performing all FDA submissions. TARGET HEALTH receives daily updates of new developments at FDA. Each week, highlights of what is going on at FDA are shared to assure that new information is expeditiously made available.

Fast Track Designation 

Fast track programs (Section 506(a)(1) of the Food Drug and Cosmetic Act) are designed to facilitate the development and expedite the review of new drugs or biologics that are intended to treat serious or life-threatening conditions and that demonstrate the potential to address unmet medical needs. The fast track classification thus does not apply to a product alone, but applies to a combination of the product and specific indication for which it is being studied. The indication includes both the condition for which the drug is intended (e.g., heart failure) and the anticipated or established benefits of use (e.g., improved exercise tolerance, decreased hospitalization, increased survival). It is therefore the development program for a specific drug for a specific indication that will receive fast track designation. 

Serious or Life-Threatening Condition 

A seriousness of a condition is generally based on its impact on such factors as survival, day-to-day functioning, or the likelihood that the disease, if left untreated, will progress from a less severe condition to a more serious one. Thus, acquired immunodeficiency syndrome (AIDS), all other stages of human immunodeficiency virus (HIV) infection, Alzheimer’s dementia, angina pectoris, heart failure, cancer, and many other diseases are clearly serious in their full manifestations. Further, many chronic illnesses that are generally well-managed by available therapy can have serious outcomes, such as inflammatory bowel disease, asthma, rheumatoid arthritis, diabetes mellitus, systemic lupus erythematosus, depression, psychoses, and many other diseases. For a condition to be serious, the condition should be associated with morbidity that has substantial impact on day-to-day functioning. For a product to be in a fast track drug development program, it must not only be used in patients with a serious condition, it must be intended to treat a serious aspect of that condition. Thus, in making a fast track determination, FDA will assess whether the development program is designed to demonstrate an effect on a serious aspect of the condition. The following examples illustrate FDA’s approach: 

  • A therapeutic product being evaluated for effects on a serious manifestation(s) or serious symptom(s) of the condition. 
  • A diagnostic product being evaluated directly for its impact on a serious aspect of the condition or if it were being evaluated for its ability to improve diagnosis or detection of the condition and scientific data provided a strong basis for a presumption that the improvements in diagnosis or detection of the condition would lead to improved outcome. 
  • A preventive product if (1) it were being evaluated for its ability to prevent a serious manifestation(s) of the condition, or (2) it were being studied for its ability to prevent the condition and it was scientifically reasonable to assume that prevention of the condition would prevent its serious consequences.  
  • A product intended to ameliorate or prevent a side effect of therapy of a condition if the side effect were serious (e.g., serious infections in patients receiving immunosuppressive therapy).  
  • A product intended and being studied for its ability to treat a condition while avoiding the side effects of currently accepted treatments of the condition if such side effects were serious (e.g., a less myelosuppressive treatment for a tumor or an anti-inflammatory drug that does not cause gastrointestinal bleeding).  

Many therapies, even those intended to treat nonserious conditions, are associated with rare, serious, adverse reactions, and new therapies, despite initial hopes, often are associated with their own set of serious reactions. Nonetheless, some adverse reactions are significant public health problems, and the development of therapies that do not cause such serious reactions would merit close attention. The Agency may designate the development of such a therapy as a fast track drug development program when (1) currently accepted therapy is widely used despite an unavoidable serious risk, (2) serious outcomes are a significant public health issue, and (3) the new therapy shows significant potential to have a substantially improved overall safety profile with at least similar efficacy. 

Demonstrating the Potential to Address Unmet Medical Needs 

Where there is no available therapy for the condition If no therapy exists for a serious condition, there is an obvious unmet medical need and a new treatment effective in that condition would meet this aspect of the criteria for fast track designation. 

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