(Complimentary Newsletter from Target Health Inc.)
October 13, 2002
Contents:
I. WHAT’S NEW
Target e*CRF International Studies and How We are
Different
II. HISTORY OF MEDICINE
X-Rays
III. DERMATOLOGY
Antimicrobial Petides and Atopic Dermatitis
IV. WOMEN'S HEALTH
Folate Deficiency Associated With Higher Early Miscarriage Risk
V. PUBLIC HEALTH
Automated External Defibrillators Use in Public Places
VI. NEUROLOGY
Mortality and Depression
VII. FOOD AND DRUG
ADMINISTRATION (FDA)
Office of the Ombudsman
TARGET HEALTH
Target e*CRF International Studies and How We are Different
A multicenter clinical trial, using an Internet-based Remote Data Entry (I-RDE) application configured by Target e*CRF, will commence in the US, Western Europe and Eastern Europe during the last quarter of 2002, This application, one of the most sophisticated we have performed to date, also contains a built-in central randomization system. The Investigator meeting will take place outside of Paris at the end of this month. Those attending from TARGET HEALTH are Laura Suciu, MS, our System Analyst and Jules Mitchel, MBA, Ph.D., company President. For this project, TARGET HEALTH also managed the pre-IND meeting, prepared and submitted the IND and performed all direct negotiations with the FDA. We are now a true eCRO.
X-Rays
When x-rays were discovered by Roentgen in 1895, he was quick to realize the importance of this mysterious new kind of ray. As early as 1896, x-rays were already being used in surgery and medicine, replacing Bell's telephonic needle probe. The telephonic needle probe could only detect metallic objects by sound and was, therefore, limited to the location of objects such as bullets. As x-ray diagnoses became more accurate, radiological techniques were gradually improved over the years and progressed from examination of the skeleton to imaging complex internal organs. The x-ray became vital in the detection of tuberculosis, for which it is still used today. Through the use of opaque substances such as barium sulfate it became possible to visualize the digestive tract and later advances in photographic techniques made visible the brain and almost all parts of the body. Meanwhile the dangers of radiation were recognized, and after 1930, safety measures were introduced to protect radiologists and patients against overexposure. In the hundred years since the discovery of x-rays, the ever-widening scope of radiology has made it a fundamental resource in medical diagnosis and treatment.
Antimicrobial Peptides and Atopic Dermatitis
Atopic dermatitis (AD), is an itchy allergic condition that often causes scratching that leaves the skin inflamed. AD affects about 15 million people in the United States and about 90% of patients wind up with long-term staphylococcus infections on their skin. The innate immune system of human skin contains antimicrobial peptides known as cathelicidins (LL-37) and -defensins. In normal skin these peptides are negligible, but they accumulate in skin affected by inflammatory diseases such as psoriasis. According to an article published in the New England Journal of Medicine (347:1151-1160), a study was performed to compare the levels of expression of LL-37 and human -defensin 2 (HBD-2) in inflamed skin from patients with atopic dermatitis and from those with psoriasis. For the study, using immunohistochemical analysis, the expression of LL-37 and HBD-2 protein was determined in skin-biopsy specimens from patients with psoriasis, atopic dermatitis, and normal control subjects. The amount of antimicrobial peptides in extracts of skin samples was also analyzed by immunodot blot analysis (for LL-37) and Western blot analysis (for HBD-2). Quantitative, real-time reverse-transcriptase-polymerase-chain-reaction (RT-PCR) assays were used to confirm the relative expression of HBD-2 and LL-37 messenger RNA (mRNA) in the skin-biopsy specimens. The peptides were also tested for antimicrobial activity against Staphylococcus aureus with the use of a colony-forming assay. Results of the analyses confirmed the presence of abundant LL-37 and HBD-2 in the superficial epidermis of all patients with psoriasis. In contrast, immunostaining for these peptides was significantly decreased in acute and chronic lesions from patients with atopic dermatitis (P=0.006 and P=0.03, respectively). These results were confirmed by immunodot blot and Western blot analyses. Real-time RT-PCR showed significantly lower expression of HBD-2 mRNA and LL-37 mRNA in atopic lesions than in psoriatic lesions (P=0.009 and P=0.02, respectively). The combination of LL-37 and HBD-2 showed synergistic antimicrobial activity by effectively killing S. aureus. The authors concluded that deficiency in the expression of antimicrobial peptides may account for the susceptibility of patients with atopic dermatitis to skin infection with S. aureus.
Folate Deficiency Associated With Higher Early Miscarriage Risk
Folic acid, a B vitamin, also known as pteroylmonoglutamic acid, is a synthetic compound used in dietary supplements and fortified foods. The term folate includes all compounds that have the vitamin properties of folic acid, including folic acid and naturally occurring compounds in food. Folate occurs naturally in beans, leafy green vegetables and citrus fruits. According to an article published in the Journal of the American Medical Association (2002;288:1867-1873), a study was performed to test the association between plasma folate levels and the risk of spontaneous abortion. The study was a population-based, matched, case-control study of case women with spontaneous abortion and control women performed from January 1996 through December 1998 in Uppsala County, Sweden. Sweden was considered an ideal country in which to conduct this study because, unlike the United States, its grain supply is not fortified with folic acid. The main outcome measure for the study was risk of spontaneous abortion vs maternal plasma folate level. For the study, 468 women who had an early miscarriage (between six and twelve weeks gestation) were compared to 921 women who were six to twelve weeks pregnant. The women were asked a series of questions about their reproductive and health histories. They also provided blood samples that were used to assess their blood folate levels. Covariate factors known to influence miscarriage risk and blood folate level, such as maternal age, education, maternal smoking, obesity, number of previous pregnancies, and country of origin, were collected. Results of the study showed that, compared with women with plasma folate levels between 2.20 and 3.95 ng/mL, women with low (<2.20 ng/mL) folate levels were at increased risk of spontaneous abortion (adjusted odds ratio [OR], 1.47; 95% confidence interval [CI], 1.01-2.14), whereas women with higher folate levels (3.96-6.16 ng/mL and >6.16 ng/mL) showed no increased risk of spontaneous abortion (OR, 0.84; 95% CI, 0.59-1.20; and OR, 0.74; 95% CI, 0.47-1.16, respectively). Low folate levels were associated with a significantly increased risk when the fetal karyotype was abnormal (OR, 1.95; 95% CI, 1.09-3.48) but not when the fetal karyotype was normal (OR, 1.11; 95% CI, 0.55-2.24) or unknown (OR, 1.45; 95% CI, 0.90-2.33). The results of the study, suggest that a 1998 mandate by the FDA to fortify grain products with folic acid to lower the risk of neural tube defects (NTDs), may now also prevent miscarriage in some women. NTDs include both spina bifida, in which a piece of the spinal cord protrudes from the spinal column, causing paralysis below the protrusion, and anencephaly, a fatal condition in which the brain fails to develop. In 1998, the Institute of Medicine recommended that all women of childbearing age receive 400 micrograms of folic acid each day.
Automated External Defibrillators Use in Public Places
According to an article published in the New England Journal of Medicine (347:1242-1247), automated external defibrillators can save lives when they are used in certain public settings. In order to evaluate the use of automated external defibrillators, a two-year prospective study was performed at three Chicago airports to assess whether random bystanders witnessing out-of-hospital cardiac arrests would retrieve and successfully use automated external defibrillators. For the study, defibrillators were installed a brisk 60-to-90-second walk apart throughout passenger terminals at O'Hare, Midway, and Meigs Field airports, which together serve more than 100 million passengers per year. The use of defibrillators was promoted by public-service videos in waiting areas, pamphlets, and reports in the media. The outcome measures of the study were 1) the time from notification of the dispatchers to defibrillation, 2) survival rate at 72 hours and 3) neurologic status at one year post cardiac arrest, and 4) the characteristics of rescuers. Results showed that over a two-year period, 21 persons had nontraumatic cardiac arrest, 18 of whom had ventricular fibrillation. With two exceptions, defibrillator operators were good Samaritans, acting voluntarily. In the case of four patients with ventricular fibrillation, defibrillators were neither nearby nor used within five minutes, and none of these patients survived. Three other patients remained in fibrillation and eventually died, despite the rapid use of a defibrillator (within five minutes). Eleven patients with ventricular fibrillation were successfully resuscitated, including eight who regained consciousness before hospital admission. No shock was delivered in four cases of suspected cardiac arrest, and the device correctly indicated that the problem was not due to ventricular fibrillation. The rescuers of 6 of the 11 successfully resuscitated patients had no training or experience in the use of automated defibrillators, although 3 had medical degrees. Ten of the 18 patients with ventricular fibrillation were alive and neurologically intact at one year. It was concluded that automated external defibrillators deployed in readily accessible, well-marked public areas in Chicago airports were used effectively to assist patients with cardiac arrest. In the cases of survivors, most of the users had no duty to act and no prior training in the use of these devices.
Mortality and Depression
It has been well-established that elderly people who are depressed are at greater risk of dying in a certain time period than their more hopeful peers. According to an article published in the British Journal of Psychiatry (2002;181:123-128), a study was performed to measure the effect of depression on mortality after controlling for cognitive decline, cardiovascular risk factors and antidepressant use. The study was a prospective cohort clinical trial which derived from data from a multicenter randomized controlled trial of moderate hypertension. A total of 2,584 participants, aged 65-75 years at study entry, were followed up for 11 years. Results showed that, depression on the SelfCARE-D scale, was associated with mortality after controlling for gender. After controlling for cardiovascular risk factors, cognitive decline and antidepressant use, depression continued to have a modest effect (odds ratio=1.43; 95% C11.03-1.98). Depression in males and in people aged under 70 years significantly increased the risk of death. It was concluded that depression was associated with mortality only after controlling for gender and that there was a modest but robust association between depression and mortality that was not explained by confounding by cardiovascular risk factors, cognitive decline or history of antidepressant use.
VII. FOOD AND DRUG ADMINISTRATION (FDA)
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.
Office of the Ombudsman
The word Ombudsman is derived from old Norse, meaning, administrative man. In todays world, an Ombudsman has come to denote someone in any organization who receives complaints, investigates and acts on them, who mediates disputes, and in general attends to problems involving interpersonal working relationships. In FDAs Center For Drug Evaluation and Research (CDER), the Ombudsman has responsibilities in addition to resolving disputes. These responsibilities include, getting feedback from inside and outside the Center 1) about the effectiveness of programs; 2) about problems that impede CDER's performance of its mission; or 3) about conflicts with its values/operating principles. The Ombudsman also advises the Center Director on ways to correct such problems. The CDER Ombudsman, parallels that of the FDA Ombudsman, but permits those who are both inside and outside the Center an avenue for getting complaints involving CDER programs resolved at a level closer to the source. The CDER Ombudsman reports directly to the Center Director, Dr. Janet Woodcock. Like the FDA Ombudsman, the CDER Ombudsman handles not only complaints but also questions about inter-center product jurisdiction. The CDER Ombudsman is the Centers contact for jurisdictional issues involving drug/device and drug/biological products. According to FDA, anyone having interactions with the Center should find the staff professional, fair, honest, courteous and helpful. FDA attempts to make every effort to honor the time frames stated in that document. FDA welcomes feedback about the effectiveness of its programs or suggestions on how to improve operations. FDA will also do their best to respond to all complaints in a timely and effective manner. If one is experiencing problems with a matter involving one of the Divisions, FDA strongly suggests that it be first discussed with the director of that Division. If one is still not satisfied with the outcome of that discussion, one may take the matter to either the Director of the Office to which the Division reports or to the Ombudsman. One may also want to consider resolving differences of a scientific, regulatory or procedural nature through mediation. The Ombudsman is prepared to mediate disputes or arrange for such mediation. Some people who contact the Ombudsman would prefer to keep their identity unknown to others in the Center. There are a few matters in which confidentiality cannot be preserved, such as allegations of criminal activity, which must be reported to the FDA Offices of Internal Affairs or Criminal Investigations. Generally, though, contact with the Ombudsman can be kept confidential, if requested. The most commonly stated reason for seeking confidentiality is the fear of retaliation. Retaliation or the threat of retaliation is regarded as a very serious violation of the rules of employee conduct, and it will not be tolerated by FDA.
TARGET HEALTH INC. is a full service CRO with fulltime staff dedicated to all aspects of Regulatory Affairs, including IND, IDE, NDA, 510(k) and PMA submissions, Clinical Research Management, Medical Writing, Internet-based Data Capture and Project Management (Target e*CRF?, Biostatistics, Data Management, Strategic Planning and Drug and Device Development. TARGET HEALTH's Pharmaceutical Advisory Dream Team (PADT) assists companies in strategic planning from discovery to market launch. Let us help you on your next project.
TARGET HEALTH INC.
261 Madison Avenue, 24th Floor
New York, NY 10016
Phone (212) 681-2100; Fax (212) 681-2105
Dr. Jules T. Mitchel, President (julesmitchel@targethealth.com)
Ms. Joyce Hays, CEO, TARGET HEALTH INC. (joycehays@targethealth.com)
?2002 Target Health Inc. All rights reserved.