In December 2008, the FDA and the Committee for Medicinal Products for Human Use (CHMP), part of the European Medicines Agency (EMEA), granted marketing authorization for degarelix, a new GnRH receptor antagonist indicated for patients with advanced, hormone-dependent prostate cancer. Degarelix used Target e*CRF for all of it’s Phase 2 and Phase 3 studies.

There are now 14 Approved Products in the US that used Target e*CRF for their clinical trial programs (3-NDAs, 1-BLA, 9-PMAs and 1-510(k)). In the US, there are currently 1 NDA and 1 PMA under review, both of which have been designated “Approvable.” In Europe, there is 1 MAA under review. There are also approvals for the same products in other countries. An NDA in the GI area was submitted this year, and this coming year, an NDA will be submitted in the area of Women’s Health as well as an NDA for an Orphan Metabolic Disease. For the latter project, Target Health will also be preparing and submitting the eCTD.
For more information about Target Health or any of its software tools for paperless clinical trials, please 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

Target Health is very pleased to announce that Target e*CRF was used in all of the Phase II and Phase III studies during the development of Degarelix.

Prostate cancer is one of the most commonly diagnosed cancers in the US. In 2004, the most recent year for which statistics are currently available, nearly 190,000 men were diagnosed with prostate cancer and 29,000 men died from the cancer. Several treatment options exist for different stages of prostate cancer including observation, prostatectomy (surgical removal of the prostate gland), radiation therapy, chemotherapy, and hormone therapy with agents that affect GnRH receptors (gonadotropin releasing hormone (GnRH) receptor inhibitors). Hormonal treatments for prostate cancer may cause an initial surge in testosterone production before lowering testosterone levels. This initial stimulation of the hormone receptors may temporarily prompt tumor growth rather than inhibiting it. Degarelix, the first new drug in several years for advanced prostate cancer, doesn’t do this. Degarelix belongs to a class of agents called GnRH receptor inhibitors. These agents slow the growth and progression of prostate cancer by suppressing testosterone, which plays an important role in the continued growth of prostate cancer. According to Richard Pazdur, M.D., director of the Office of Oncology Drug Products at FDA. Prostate cancer is the second leading cause of cancer death among men in the United States and there is an ongoing need for additional treatment options for these patients. The efficacy of degarelix was established in a clinical trial in which patients with prostate cancer received either degarelix or leuprolide, a drug currently used for hormone therapy in treating advanced prostate cancer. Degarelix treatment did not cause the temporary increase in testosterone that is seen with some other drugs that affect GnRH receptors. In fact, nearly all of the patients on either drug had suppression of testosterone to levels seen with surgical removal of the testes. The most frequently reported adverse reactions in the clinical study included injection site reactions (pain, redness, and swelling), hot flashes, increased weight, fatigue, and increases in some liver enzymes. Degarelix is manufactured for Ferring Pharmaceuticals Inc., Parsippany, N.J., by Rentschler Biotechnologie Gmbh, Laupheim, Germany.

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.

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

Coronary artery calcification is a subclinical predictor of coronary heart disease. Recent studies have found that sleep duration is correlated with established risk factors for calcification including glucose regulation, blood pressure, gender, age, education, and body mass index. As a result a study published in the Journal of the American Medical Association (2008;300:2859-2866), was performed to determine whether objective and subjective measures of sleep duration and quality are associated with incidence of coronary calcification and whether calcification risk factors mediate the association. The study design was an observational cohort of home monitoring in a healthy middle-aged population of 495 participants from Chicago who participated in the Coronary Artery Risk Development in Young Adults (CARDIA) study. The study included Caucasian and African American men and women, who were aged 35-47 years of age at year 15 of the study in 2000-2001, with follow-up data at year 20 in 2005-2006. Potential confounders (age, gender, race, education, apnea risk, smoking status) and mediators (lipids, blood pressure, body mass index, diabetes, inflammatory markers, alcohol consumption, depression, hostility, self-reported medical conditions) were measured at both baseline and follow-up. Sleep metrics (wrist actigraphy measured duration and fragmentation, daytime sleepiness, overall quality, self-reported duration) were examined for association with incident calcification. Participants had no detectable calcification at baseline. The main outcome measure was coronary artery calcification as measured by computed tomography in 2000-2001 and 2005-2006. The incidence of new calcification over that time was the primary outcome. Results showed that the 5-year calcification incidence was 12.3% (n = 61). Longer measured sleep duration was significantly associated with reduced calcification incidence (adjusted odds ratio, 0.67 per hour, P = .01). The cutoff for risk appeared to be at <5 hours of sleep. No potential mediators appreciably altered the magnitude or significance of sleep. Alternative sleep metrics were not significantly associated with calcification. According to the authors, longer measured sleep is associated with lower calcification incidence independent of examined potential mediators and confounders.

Anxiety disorders are common psychiatric conditions affecting children and adolescents. Although cognitive behavioral therapy and selective serotonin-reuptake inhibitors have shown efficacy in treating these disorders, little is known about their relative or combined efficacy. As a result, a study published in the New England Journal of Medicine (2008;359:2753-2766), was performed to evaluate the effects of a combination of sertraline (Zoloft, Pfizer) and cognitive behavioral therapy, cognitive therapy alone, sertraline alone or placebo in 488 children between the ages of 7 and 17 years who had a primary diagnosis of separation anxiety disorder, generalized anxiety disorder, or social phobia. Treatments included 14 sessions of cognitive behavioral therapy, sertraline (at a dose of up to 200 mg per day), a combination of sertraline and cognitive behavioral therapy, or a placebo drug for 12 weeks in a 2:2:2:1 ratio. Categorical and dimensional ratings of anxiety severity and impairment were administered at baseline and at weeks 4, 8, and 12. Results showed that the percentages of children who were rated as very much or much improved on the Clinician Global ImpressionImprovement scale were 80.7% for combination therapy (P<0.001), 59.7% for cognitive behavioral therapy (P<0.001), and 54.9% for sertraline (P<0.001); all therapies were superior to placebo (23.7%). Combination therapy was superior to both monotherapies (P<0.001). Results on the Pediatric Anxiety Rating Scale documented a similar magnitude and pattern of response; combination therapy had a greater response than cognitive behavioral therapy, which was equivalent to sertraline, and all therapies were superior to placebo. Adverse events, including suicidal and homicidal ideation, were no more frequent in the sertraline group than in the placebo group. No child attempted suicide. There was less insomnia, fatigue, sedation, and restlessness associated with cognitive behavioral therapy than with sertraline. The authors concluded that both cognitive behavioral therapy and sertraline reduced the severity of anxiety in children with anxiety disorders but that a combination of the two therapies had a superior response rate.

A new study using a single compound to increase the lifespan of obese mice, found that the drug reversed nearly all of the changes in gene expression patterns found in mice on high calorie diets–some of which are associated with diabetes, heart disease, and other significant diseases related to obesity. The research, led by investigators at Harvard Medical School and the National Institute on Aging, is the first time that the small 1) ___, resveratrol has been shown to offer survival benefits in a mammal. Mice are much closer evolutionarily to humans than any previous model organism treated by this molecule, which offers hope that similar impacts might be seen in humans without negative side-effects. After six months, resveratrol essentially prevented most of the negative effects of the high calorie diet in mice. Resveratrol is found in red wines and produced by a variety of plants when put under stress. Since 2003, resveratrol has been shown to extend the lifespan of worms and flies by nearly 30%, and fish by almost 60%. It has also been shown to protect against Huntington’s disease in two different animal models (worms and mice).”The healthspan benefits we saw in the obese mice treated with resveratrol, such as increased insulin sensitivity, decreased glucose levels, healthier heart and liver tissues, are positive clinical 2) ___ and may mean we can stave off in humans, age-related diseases such as type 2 diabetes, heart disease, and 3) ___, but only time and more research will tell,” says Harvards David Sinclair MD, who is also a co-founder of Sirtris, a company which is currently in a phase 1b trial in humans with diabetes using an enhanced, proprietary formulation of 4) ___. [Harvard has license and equity interests with Sirtris, which is not a public company.] Investigators identified resveratrol while looking for compounds that activate Sir2, an 5) ___ linked to lifespan extension in yeast and other lower organisms. “The median lifespan increase, in mice, we are seeing is about 15% at this point,” says Sinclair. “We won’t have final lifespan numbers until all of the mice pass away, and this particular strain of mouse generally lives for two-and-a-half-years. So we are around five months from having final numbers, but there is no question that we are seeing increased longevity. The team also found that the HCR fed mice had a much higher 6) ___ of life, outperforming the HC fed mice on motor skill tests. “The mice on resveratrol have not just been living longer,” says Sinclair. “They are also living more active, better lives. Their motor skills actually show improvement as they grow older.” Mice on a rotarod also showed improved motor function with age over its HC fed counterparts. Researchers watched how well the mice did walking on a rotarod, similar to walking on a log in the water, a common measure of balance and motor coordination. “We made a striking observation,” says Sinclair. “Resveratrol opposed the effects of high caloric intake in 144 out of 153 significantly altered pathways. In terms of gene expression and pathway comparison, the resveratrol fed group was more similar to the standard diet fed group than the high calorie group. “The research team found that levels of PGC-1alpha were three-fold lower in the HCR fed mice than in the HC mice, consistent with what would be expected when SIRT1 was being activated by resveratrol. This work demonstrates that there may be tremendous 7) ___ benefits to unlocking the secrets behind the genes that control our longevity.

ANSWERS: 1) molecule; 2) indicators; 3) cancer; 4) resveratrol; 5) enzyme; 6) quality; 7) medical