(Complimentary Newsletter from Target Health Inc.)
15 March 2004
I. WHAT'S NEW?
FDA
Submissions
II. HISTORY OF MEDICINE
Harvey Cushing - Pediatric Neurosurgeon
III. WOMEN'S
HEALTH
Colorectal Cancer and Estrogen Plus Progestin
Use
IV. EPIDEMIOLOGY
Kidney Disease
Awareness Among African Americans
V. CARDIOLOGY
Heart Failure Outcome and the
Use of an Implantable Cardiac Defibrillator (ICD)
VI. CARDIOLOGY
Statins and Cardiovascular Event Risk -
Pravachol vs. Lipitor
VII. FDA
FDA Approves Sensipar (cinacalcet) To Treat Secondary
Hyperparathyroidism
FDA Submissions
Over the last six months, Target Health has been directly involved with one NDA and one PMA submission, one original IND submission, five pre-IND meeting projects, three Orphan Drug Designation Requests, and two 510(k) programs. A good regulatory foundation is critical for your drug development program. For more information on our regulatory and eCRO services, please contact Dr. Jules T. Mitchel (julesmitchel@targethealth.com).
Harvey Cushing - Pediatric Neurosurgeon
Development of posterior fossa surgery remains Harvey Cushing's hallmark contribution
to pediatric neurosurgery. During the era before Cushing, posterior fossa (brainstem
glioma) lesions were considered inoperable, and only osseous decompressive surgery
was offered. The evolution of Cushing's surgical expertise from subtemporal
decompressions (removal of a piece of the cranium, usually in the subtemporal
region, with incision of the dura, to relieve intracranial pressure) to total
extirpation of vascular fourth ventricular tumors, combined with a dramatic
decrease in his operative mortality rate, reflects the maturation of modern
neurosurgical techniques. A comprehensive review of the medical records of Cushing's
pediatric patients treated between 1912 and 1932 revealed that procedures such
as lateral ventricular puncture (to decrease cerebellar herniation), transvermian
approach to midline tumors, and electrocoagulation were the key factors punctuating
the path to his pioneering achievements in posterior fossa surgery. The outcome
of such operations was improved by his recognition of the importance of tumor
mural nodule in cyst recurrence, as well as elucidation of the histogenesis
of pediatric posterior fossa tumors to tailor treatment including radiotherapy.
III. WOMEN'S HEALTH
Colorectal Cancer and Estrogen Plus Progestin Use
Although the Women's Health Initiative (WHI) trial of estrogen plus progestin in postmenopausal women identified more overall health risks than benefits among women in the hormone group, the use of estrogen plus progestin was associated with a significant decrease in the risk of colorectal cancer. According to an article published in the New England Journal of Medicine (2004;350:991-1004), an analysis was performed to evaluate the features of the colorectal cancers that developed and their relation to the characteristics of the participants. For the study, 16,608 postmenopausal women who were 50 to 79 years of age, and had an intact uterus, were randomly assigned to a combination of conjugated equine estrogens (0.625 mg per day) plus medroxyprogesterone acetate (2.5 mg per day) or placebo. The main outcome measures were the incidence, stages, and types of colorectal cancer, as determined by blinded central adjudication. Results showed that there were 43 invasive colorectal cancers in the hormone group and 72 in the placebo group (P=0.003). The invasive colorectal cancers in the hormone group were similar in histologic features and grade to those in the placebo group but with a greater number of positive lymph nodes (3.2?.1 vs. 0.8?.7; P=0.002) and were more advanced (regional or metastatic disease, 76.2% vs. 48.5%; P=0.004). In exploratory analyses, women in the hormone group with antecedent vaginal bleeding had colorectal cancers with a greater number of positive nodes than women in the hormone group who did not have vaginal bleeding (3.8?.3 vs. 0.7?.5 nodes, P=0.006). According to the authors, relatively short-term use of estrogen plus progestin was associated with a decreased risk of colorectal cancer. However, colorectal cancers in women who took estrogen plus progestin were diagnosed at a more advanced stage than those in women who took placebo.
Kidney Disease Awareness Among African
Americans
Epidemic numbers of people, roughly 20 million, have
kidney disease and another 400,000 or more are already on dialysis or have a
kidney transplant because their kidneys failed. The cost to taxpayers, insurers,
and patients was an estimated $22.8 billion in 2001 alone. While anyone can
develop kidney disease, African Americans are the most vulnerable. An estimated
36 in 100,000 African Americans versus 11 in 100,000 Whites were treated for
kidney failure in 2001. African Americans have four times the risk of kidney
failure and those with diabetes have up to six times the risk compared to White
counterparts. But the biggest disparity is among African American men ages 25 to
44, who are 20 times more likely to develop kidney failure compared to
corresponding Whites. Although kidney failure and its leading causes
disproportionately affect African Americans, according to the first NIH study to
assess the group's knowledge and awareness about kidney disease, African
Americans are largely unaware of their high risk and of preventive measures. For
the study, the National Kidney Disease Education Program (NKDEP) polled more
than 2,000 African Americans aged 30 and older living in Atlanta; Baltimore;
Cleveland; and Jackson, Mississippi, in April 2003, shortly before local
coalitions launched a year-long pilot program "You Have the Power to Prevent
Kidney Disease." Results of the poll showed that while 90% of African Americans
surveyed had heard about kidney disease, only 15% felt their personal risk for
developing the disease was higher than average and fewer knew specifically how
to prevent it. This gap in awareness raises serious concern, especially because
44% of those interviewed had at least one of the major risk factors for kidney
disease (i.e. diabetes, high blood pressure or a blood relative with the
disease). In addition, only 17% named kidney disease as a consequence of
diabetes and only 8% named it as a consequence of hypertension. These two
diseases are the leading causes of kidney failure in the United States and
account for 70% of kidney failure among African Americans. The poll also found
that 52% of people knew at least one major cause of kidney disease, but 48% were
unable to name any cause and others named incorrect causes such as drinking
sodas. When asked about symptoms of early kidney disease, 13% correctly said
that there are none, while 64% expected early symptoms to include difficulty
urinating, general pain and frequent urination. The study will be repeated in
May to measure changes in knowledge and awareness.
Heart Failure Outcome and the Use of an Implantable
Cardiac Defibrillator (ICD)
Heart failure affects about 5
million Americans. It develops over time as the heart loses its ability to pump
blood through the body. It can be caused by various conditions, including heart
attack. Symptoms include feeling tired, having trouble breathing, and swelling
(edema), usually in the legs and ankles. It is estimated that about 50% of
deaths in heart failure are sudden deaths and are probably due to a ventricular
tachyarrhythmia, or rapid heartbeats in one of the lower chambers. In sudden
death, the heart stops abruptly. The "Sudden Cardiac Death in Heart Failure"
study (SCD-HeFT) tested whether an implantable cardiac defibrillator (ICD) that
provides a shock without pacing impulses or an antiarrhythmic drug, would help
prevent sudden death in heart failure patients. An ICD is put under the skin of
the chest and sends an electric signal to correct a potentially fatal
arrhythmia. An antiarrhythmic drug works by preventing the occurrence of an
irregular heartbeat. Preliminary results from the SCD-HeFT study presented at
the American College of Cardiology Annual Scientific Session 2004 in New
Orleans, found that an ICD significantly reduces deaths in heart failure
patients, while treatment with the antiarrhythmic drug amiodarone does not. The
study had a relatively high percentage of women and minorities, and was larger
and lasted longer than earlier trials of sudden death in heart failure patients.
The study involved 2,521 participants, who were randomly assigned to one of
three treatment arms 1) placebo (n=847), amiodarone (n=845) and ICD (n=829). The
mean follow-up was almost 4 years. Patient enrollment began in September 1997
and patient follow-up ended in October 2003. Participants were enrolled through
148 hospitals, clinics, and academic centers in the United States, Canada, and
New Zealand. The participants had moderate to severe heart failure - New York
Heart Association classes II and III. Classes range from I to IV. Class II
patients have trouble breathing or feel tired after exercise, such as climbing
stairs; class III patients have such heart failure symptoms while performing
minimal activities, such as walking on level ground. Study participants ranged
in age from 19 to 90; the median age was 60. Seventy-seven percent were men and
23% women. Seventy-seven percent were white, 17% African American, and about 6%
other minorities. Fifty-two percent had heart failure caused by heart attack
(myocardial infarction) and 48% had heart failure due to a different cause, such
as a viral infection of the heart. Thirty percent had diabetes and 15% had had
at least one episode of diagnosed atrial fibrillation when they entered the
study. At the end of the study, there were 666 deaths overall: 182 (22%) in the
ICD group, 240 (28%) in the amiodarone group, and 244 (29%) in the placebo
group. The benefit from implantable defibrillator therapy appeared to be
strongest in those with moderate heart failure at enrollment. Amiodarone therapy
appeared to have a detrimental effect in those with severe heart failure at
enrollment. The implantable defibrillator therapy reduced deaths for patients
whether their heart failure resulted from heart attack or a different cause.
Statins and Cardiovascular Event Risk - Pravachol vs. Lipitor
According to an article published online by the New England Journal of Medicine and presented at the annual meeting of the American College of Cardiology I New Orleans last week, lipid-lowering therapy with statins reduces the risk of cardiovascular events. For the study, 4,162 patients were enrolled who had been hospitalized for an acute coronary syndrome within the preceding 10 days. Patients were randomized to either 40 mg of pravastatin (Pravachol, BMS) daily (standard therapy) with 80 mg of atorvastatin (Lipitor, Pfizer) daily (intensive therapy). The primary end point was a composite of death from any cause, myocardial infarction, documented unstable angina requiring rehospitalization, revascularization (performed at least 30 days after randomization), and stroke. The study was designed to establish the noninferiority of pravastatin as compared with atorvastatin with respect to the time to an end-point event. Follow-up lasted 18 to 36 months (mean, 24). Results showed that the median LDL cholesterol level achieved during treatment was 95 mg per deciliter (2.46 mmol per liter) in the standard-dose pravastatin group and 62 mg per deciliter (1.60 mmol per liter) in the high-dose atorvastatin group (P<0.001). Kaplan-Meier estimates of the rates of the primary end point at two years were 26.3% in the pravastatin group and 22.4% in the atorvastatin group, reflecting a 16% reduction in the hazard ratio in favor of atorvastatin (P=0.005; 95% confidence interval, 5 to 26%). The study did not meet the prespecified criterion for equivalence but did identify the superiority of the more intensive regimen. It was concluded that among patients who have recently had an acute coronary syndrome, an intensive lipid-lowering statin regimen provides greater protection against death or major cardiovascular events than does a standard regimen. These findings indicated that such patients benefit from early and continued lowering of LDL cholesterol to levels substantially below current target levels.
TARGET HEALTH excels in Regulatory Affairs and works closely with many of its clients and FDA and performs 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.
FDA Approves Sensipar (cinacalcet) To Treat Secondary Hyperparathyroidism
Elevated levels of parathyroid hormone (PTH), the hallmark of secondary hyperparathyroidism, are associated with altered metabolism of calcium and phosphorus, bone pain, fractures, and an increased risk for cardiovascular death. FDA has recently approved Sensipar (cinacalcet), a drug to treat secondary hyperparathyroidism in patients with chronic kidney disease on dialysis, as well as hypercalcemia in patients with parathyroid cancer. Cinacalcet is the first drug in the class of compounds known as calcimimetics to be approved by the FDA. It is approved as a treatment for secondary hyperparathyroidism in patients with chronic kidney disease on dialysis. Treatment with cinacalcet lowers serum levels of PTH as well as the calcium (x) phosphorus ion product. The calcium (x) phosphorus ion product is a measure of the amount of calcium and phosphorus in the blood, and when elevated, causes harmful deposition of calcium in various parts of the body. Cinacalcet is also approved for the treatment of hypercalcemia associated with parathyroid carcinoma, a rare cancer that causes significant elevations in serum calcium levels. Elevated levels of serum calcium can cause mental confusion, lethargy, dehydration, nausea, vomiting, constipation, and kidney damage. In three 6-month cinacalcet clinical trials of more than 1,000 patients with chronic kidney disease receiving dialysis, the most commonly reported side effects were nausea and vomiting, which occurred in 31% and 27%, respectively, of cinacalcet-treated patients, compared with 19% and 15%, respectively, of patients who received placebo. Treatment of patients with chronic kidney disease with cinacalcet was also associated with the development of low serum calcium levels in a significant number of patients. Frequent monitoring of patients' calcium levels is therefore recommended in the cinacalcet labeling. Amgen, of Thousand Oaks, Calif. will market cinacalcet by the trade name, Sensipar.
VIII. TARGET HEALTH
TARGET HEALTH INC. (www.targethealth.com) is a full service e*CRO with fulltime staff dedicated to all aspects of drug and device development. Areas of expertise include Regulatory Affairs, comprising, but not limited to, IND, IDE, NDA, PMA and 510(k) submissions, execution of Clinical Trials, Project Management, Biostatistics and Data Management, Web Trials, utilizing Target e*CRF™™, our proprietary Internet-based Remote Data Entry (I-RDE? system, and Medical Writing. TARGET HEALTH's Pharmaceutical Advisory Dream Team (PADT) assists companies in strategic planning from Discovery to Market Launch. Let us help you on our next project.
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