(Complimentary Newsletter from Target Health Inc.)
August 5, 2001
Contents:
I. WHAT'S NEW
Orphan Drug Designation Approval
Internet-Based Clinical Trials - Electronic Data Capture
II. HISTORY OF MEDICINE
Neonatal Jaundice I
II. NEUROLOGY
Surgical Management of Temporal-Lobe Epilepsy
Migraine
IV. WOMEN'S HEALTH
Hormone Replacement and Heart Disease
Premature Birth and Periodontal Disease
V. GENETICS
Risk of Hypertrophic Cardiomyopathy (HCM)
VI. GASTROENTEROLOGY
Aspirin and Helicobacter Pylori
VII. FDA
The Fantastic Voyage
TARGET HEALTH
Orphan Drug Designation Approval
TARGET HEALTH is pleased to announce that one of its clients has received Orphan Drug Designation for one of its products. TARGET HEALTH prepared the Request For Orphan Drug Designation back in March. As part of TARGET HEALTH's broad expertise in Regulatory Affairs, we also recently prepared and submitted two Requests For Designation. These requests, which are submitted to the Office of the Commissioner at FDA, allows the FDA to designate products as Drug, Biologics or Devices when it is not clear which FDA division will be the primary reviewer.
Internet-Based Clinical Trials - Electronic Data Capture
Some of our readers have asked what is the largest study TARGET HEALTH has performed to date. We are pleased to announce that our largest Internet-based electronic data capture and management system trial using Target e*CRF™ has enrolled 244 centers in the US. Up to 30 patients will be enrolled in each center. An international study based in Israel begins this week. We have one of the best and most user-friendly system in the business. We are fully integrated; we require no software installation or high speed modems; we can use your database; we use no outside vendors; it takes 15 minutes to learn to operate.
Neonatal Jaundice
In 1785 Jean Baptiste Thimotee Baumes was awarded a prize from the University of Paris for his work describing the clinical course in 10 jaundiced infants. Subsequently, in 1847, Jaques Hervieux described very detailed and systematic pathoanatomical findings of jaundice which in many respects was a landmark study. Hervieux had autopsy data on 44 jaundiced infants and clinical observations on many others. A number of his clinical observations such as 1) the essentially benign nature of neonatal jaundice in most cases, 2) the appearance of neonatal jaundice during the first 2 to 4 days of life as well as its disappearance within 1 to 2 weeks, and 3) the cephalocaudal progression of jaundice, are still thought to be accurate today. Johannes Orth was an assistant to the famous Virchow in Berlin, when he published the results of an autopsy of a jaundiced term infant in 1875 . The brain was notable for an intense yellow staining of the basal ganglia, the wall of the third ventricle, the hippocampus, and the central parts of the cerebellum. While the contribution of Orth was limited to this single case report, in 1903 Christian Schmorl presented the results of his autopsies of 120 jaundiced infants to the German Society for Pathology. All of these infants' brains were jaundiced, but only 6 cases demonstrated a staining phenomenon similar to that previously described by Orth. Schmorl coined the term kernicterus (jaundice of the basal ganglia) for this staining pattern.
Surgical Management of Temporal-Lobe Epilepsy
According to an article published in The New England Journal of Medicine (N Engl J Med 2001;345:311-318,365-367), there is now robust evidence that surgery for poorly controlled temporal-lobe epilepsy is superior to prolonged medical therapy. For the study, 80 patients whose seizures were poorly controlled with medication, were enrolled in a clinical trial and randomly assigned to either immediate surgery or to the usual 1-year waiting list for surgery and treatment with antiepileptic drugs. Four of the patients assigned to surgery did not undergo surgery. Results showed that In the surgical group, 58% of patients were free of seizures impairing awareness at one year, compared with 8% in the medical group (p < 0.001). Quality of life, as measured with the Quality of Life in Epilepsy Inventory-89, was also significantly better in the surgical group (p < 0.001). According to the authors, for every two patients undergoing surgery, one patient becomes free of seizures which impair awareness at one year. This compares extremely favorably with almost any other surgical procedure of the nervous system. For example, to prevent one stroke, there is a need to operate on 10 people. After one year, 56.4% of those treated with surgery were employed or attending school, compared with 38.5% of those in the medical group.
Migraine
According to an article published in Cephalalgia (2001;21:584-595), migraine-type headaches that are unremitting or last more than 72 hours make up the largest subgroups of headaches classified by current International Headache Society (IHS) criteria as "atypical migraine." It is now recommend that these subgroups be recognized separately in the IHS criteria. For the study, headache diagnoses were assigned to 382 adult headache patients using the Structured Diagnostic Interview for Headache. Patients with atypical migraine accounted for 36% of the migraine diagnoses, but none met IHS criteria for tension-type headache. Each of the 83 atypical migraine patients fell into one of five distinct subgroups. The two largest subgroups were unremitting migraine and migraine exceeding 72 hours' duration. The third-largest subgroup included migraines lasting less than 4 hours. The remainder were migraines with atypical pain characteristics or without the usual associated non-pain symptoms. Accordingly, the authors suggest two revisions to the IHS diagnostic classification of migraine. The first would be to decrease the minimum headache duration criterion from 4 hours to 2 hours. The second would be to develop criteria for "episodic migraine" and "chronic migraine." The authors conclude that with these revisions, the designation of atypical migraine would be more precisely reserved for those patients with headaches that are truly atypical in clinically meaningful ways.
Hormone Replacement and Heart Disease
According to an article published in the journal Obstetrics and Gynecology (Obstet Gynecol 2001;98:205-211), low-dose daily estrogen replacement therapy combined with biannual progestin administration is a viable alternative to daily treatment with both hormones for postmenopausal women. For the study, outcomes were assessed in 138 women, 55 to 75 years of age, who switched from a standard hormone replacement strategy that included 0.625 mg of estrogen plus 5 mg or 10 mg progestin daily to one consisting of 0.3 mg of estrogen daily with progestin every 6 months at 10 mg daily for 14 days. Of the 125 women who underwent an endometrial biopsy one year after beginning the new regimen, only two had endometrial hyperplasia. Scheduled and unscheduled bleeding occurred in 44% and 9.4% of these women, respectively. An increase in baseline vasomotor score of 2 U or greater was reported by 20% of women at 6 months and by 17% of women at 1 year. According to the authors, treatment with half the standard dose of estrogen causes very little stimulation of the lining of the uterus. However, because there still is a small risk of endometrial hyperplasia, it still makes sense to oppose the effects of estrogen with progestin.
Premature Birth and Periodontal Disease
According to an article published in the Journal of the American Dental Association (JADA 2001;132:875-880), pregnant women with periodontitis have an increased risk of delivering prematurely. For this prospective study, 1,313 pregnant women had complete periodontal, medical and behavioral assessments between 21 and 24 weeks' gestation. Medical records were then reviewed after delivery to determine the gestational age at birth. Results showed that 13.6% of the women studied gave birth prematurely (before 37 weeks' gestation). Subjects with severe or generalized periodontitis had adjusted odds ratios of 4.45 for preterm delivery before 37 weeks' gestational age. The adjusted odds ratio increased to 5.28 for those who gave birth before 35 weeks, and to 7.07 among women who gave birth before 32 weeks. According to the authors, in the future, it may be possible to reduce preterm births if it is possible to detect patients at higher risk with a periodontal examination.
Risk of Hypertrophic Cardiomyopathy (HCM)
According to two studies published in the Journal of the American College of Cardiology (Am Coll Cardiol 2001;38:315-334), the number of genetic mutations responsible for hypertrophic cardiomyopathy (HCM) is greater than previously thought, and genetically predisposed individuals with normal-sized hearts in adolescence may still develop left ventricular hypertrophy (LVH) later in life. In the first study, the presence of myosin-binding protein C gene (MYBPC3) mutations was assessed in 110 consecutive, unrelated patients with HCM and their family members. Thirteen different mutations were found in 15 index patients and 14 family members. The mutation types included one nonsense, four missense, three splicing, and five small deletions and insertions. All but two of the mutations were newly identified and two were probably founder mutations. The 16 carriers of mutations that led to protein truncations appeared to have more severe HCM manifestations than the 9 carriers of missense mutations or in-frame deletions. In the second study, the age-dependent phenotypic expression of HCM was evaluated in five adults with MYBPC3 mutations and a normal left ventricular wall thickness at baseline. Serial echocardiographic examination over 4 to 6 years revealed that three of the five subjects developed LVH in mid-life. According to the authors, it was previously thought that a normal echocardiogram at 17 or 18 years of age ruled out the risk of developing HCM in family members of patients with HCM. However, the current findings suggest that the manifestations of HCM can develop later in life and that physicians cannot rely solely on a normal finding in adolescence to rule out future disease.
Aspirin and Helicobacter Pylori
According to an article published in The American Journal of Gastroenterology (Am J Gastroenterol 2001;96:1751-1757), while aspirin and Helicobacter pylori infection have each been linked to gastric mucosal injury, it seems that these factors also interact to increase the risk of damage. For the study, 29 healthy subjects with H. pylori infection and 32 similar subjects without infection were randomized to receive placebo or low-dose aspirin therapy for 45 days. Results of endoscopic examinations showed the presence of aspirin-related erosive disease in 50% of the infected subjects, but only in 16% of the uninfected subjects. Furthermore, aspirin caused significantly greater gastric antrum damage in the infected subjects than in the uninfected subjects. Two of the aspirin-treated infected subjects developed antral ulcers. The differences in aspirin-induced damage could not be accounted for by differences in prostaglandin levels since infected and uninfected subjects showed similar reductions in prostaglandin synthesis. According to the authors, these findings indicate that the inflammation that is present with H. pylori infection predisposes to more damage from aspirin. They add that the implication from the current findings is that if one could identify these high-risk patients and eradicate the infection prior to aspirin therapy, one may reduce the risk of significant GI bleeding and other ulcer complications
TARGET HEALTH excels in Regulatory Affairs and works closely with many of its clients and FDA. 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.
Guideline - The Clinical Studies Section of Product Labeling
The FDA has issued a draft guidance on the format and content of the Clinical Studies section of product labeling. The guidance is intended to help applicants decide (1) what studies should be included in the Clinical Studies section, (2) how to describe individual studies, and (3) how to present study data, including presentation of data in graphs and tables. The guidance is intended to make the Clinical Studies section of labeling more useful to prescribers and to promote consistency in the content and format of the section across drug product classes and within drug classes and indications. The guidance also calls attention to advertising and promotional implications of the data and statements. The overriding objective in labeling is to provide the information that is most useful to prescribers in treating their patients. In some cases, making clinical studies information more useful could cause significant departures from past labeling practices. The Clinical Studies section should provide a concise, accurate summary of the evidence supporting effectiveness. This information will generally be derived from the adequate and well-controlled studies that supported effectiveness for the approved indication. Redundant information should be omitted or described briefly without detail. If there are multiple studies that address the same effectiveness issue, the subset selected for presentation should ordinarily reflect the overall conclusions derived from the studies as a whole. However, study results that are inconsistent with the overall conclusions (e.g., absence of a treatment effect) should be included when they provide important information about drug effectiveness that is not otherwise available (e.g., information about a population subset, dose response, or the limitations of effectiveness). For a copy of the Guidance, please email to julesmitchel@targethealth.com.
TARGET HEALTH INC. is a full service CRO with full-time 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 HEATH'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.
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Dr. Jules T. Mitchel, President (julesmitchel@targethealth.com)
Ms. Joyce Hays, CEO, TARGET HEALTH INC. (joycehays@targethealth.com)
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