On Target - Weekly Journal, Issue December 26th, 1999

I	..	WHAT'S NEW
II		HISTORY OF MEDICINE Pellagra
III		WOMEN'S HEALTH High-Risk Pregnancy
IV		PULMONARY DISEASE Asthma
V		ANTIMICROBIALS AND THE PUBLIC HEALTH Mad Cow Disease
VI		NEUROLOGY Diabetes and Dementia
VII		DRUG APPROVAL Celebrex - Intestinal Polyps
VIII		FDA User Fees
IX		TARGET HEALTH INC.

Happy New Year to you and your family. May the New Year bring you health, peace and success. With the upcoming holiday season, TARGET HEALTH will be taking a breather between Christmas and New Year's. We will be checking our voice mail but not necessarily all of our e-mail.

In 1914, pellagra was thought to be an infectious disease. In order to find a cure for pellagra, Dr. Joseph Goldberger traveled throughout the South observing employees in hospitals, asylums, and orphanages. Goldberger never "contracted" the disease and concluded that diet and pellagra were related. He wrote in September 1914, "No pellagra develops in those who consume a mixed, well-balanced diet." Carefully controlled dietary studies in orphanages confirmed this theory and in a classic experiment in a convict camp in Mississippi, Goldberger produced the disease experimentally by diet. Additional experiments on himself and co-workers showed that it was impossible to transmit the disease from one person to another. Goldberger was convinced that the solution lay with chemists and experimental nutritionists. Foods were analyzed, and Goldberger and his associates began experimental studies with dogs. In 1926, the pellagra-preventive factor was reported to be a member of the B-group of vitamins. In October 1937, a researcher at the University of Wisconsin identified nicotinic acid (niacin) as the curative factor for pellagra. See: Goldberger, Joseph and G.A. Wheeler. The Experimental Production of Pellagra in Human Subjects by Means of Diet. Washington: Government Printing Office, 1920. (Hygienic Laboratory Bulletin)

TARGET HEALTH has current programs in the areas of infertility and female sexual dysfunction. Accomplishments include an NDA approval in the area of infertility, an IDE and successful completion of a Phase 1 study in adhesion prevention in gynecological surgery, an IDE and successful completion of a clinical trial for home-use non-stress testing (NST) in high-risk pregnancies, and a pregnancy diagnostic.

According to an article published in Obstetrics and Gynecology (Obstet Gynecol 1999;94:929-934), a maternal serum screening factor has been identified which provides positive predictive values of adverse obstetric outcomes in both high- and low-risk pregnancies. In a multicenter clinical trial, women were studied whose fetuses had either no chromosomal abnormalities or neural tube defects. Women were divided into three groups and maternal serum alpha-fetoprotein levels and/or maternal serum hCG levels were evaluated in all study subjects. The three groups were comprised of women without pre-existing risk for poor outcome, women at elevated risk for poor obstetric outcome and a control group with normal maternal serum values. It was found that fetal or neonatal death, pregnancy-induced hypertension, placental abruption, placenta previa, preterm delivery, delivery of infants with low birth weights and complications during the third stage of labor occurred significantly more often in patients with elevated values and low-risk than in women with normal values and without pre-existing risk factors. In women at high-risk for poor outcomes, the presence of elevated serum marker levels did not relate to further increase in risk. It was hypothesized that the negative predictive value of maternal serum screening is too low for serum screening to be used as a screening instrument for adverse pregnancy outcome, but that women at low-risk of adverse obstetric outcome with unexplained high levels of maternal serum alpha-fetoprotein and/or serum hCG levels need to be followed closely during pregnancy.

TARGET HEALTH currently is managing an early development project in Chronic Obstructive Pulmonary Disease (COPD). Another project in asthma is on the horizon. Both projects are in the pre-clinical phase and TARGET HEALTH is planning to take both projects to the NDA.

According to an article published in The New England Journal of Medicine (N Engl J Med 1999;341:1966-1973, 2006-2008), treatment with recombinant humanized monoclonal antibody (rhuMAb-E25), which blocks IgE from binding to mast cells and basophils, leads to a reduction in symptoms in patients with allergic asthma. In the study, 317 allergic asthmatics who required corticosteroids were randomized to treatment with either high- or low-dose intravenous rhuMAb-E25 or placebo. The high dose consisted of 5.8 mcg/kg body weight per nanogram of IgE per milliliter, and the low dose consisted of 2.5 mcg/kg per IgE ng/mL. A total of two doses were given during the first 7 days, and treatment continued at the rate of one dose every 2 weeks for 20 weeks. Subjects continued with their oral or inhaled corticosteroids for 12 weeks and, thereafter, their corticosteroid doses were tapered, and in some cases stopped. The mean asthma symptom score, based on a 7-point scale, was 4.0 at baseline. Evaluation at 12 weeks showed that the average score was 2.8 in both treatment groups versus 3.1 in the placebo group. At 20 weeks, both treatment groups scored 2.7 versus 2.9 in the placebo group. In addition, more patients in the treatment groups were able to discontinue or reduce corticosteroid treatment. At 20 weeks, it was observed that serum free IgE concentrations dropped by more than 95% in the treatment groups.

Bovine spongiform encephalopathy (BSE) belongs to a group of diseases known as the transmissible spongiform encephalopathies (TSE's), which includes Creutzfeldt-Jakob disease and scrapie. A key feature of TSE's is the formation of plaques in the brain, resulting in a spongiform appearance.

According to an article published in the journal Infection and Immunity (Infection and Immunity, 1999, 67:6591-6595), BSE, also known as "mad cow disease," could be an autoimmune disease caused by a bacterium commonly found in the soil. In the study, high numbers of antibodies to the bacterium Acinetobacter calcoaceticus were found in serum samples taken from 29 cattle confirmed to have BSE while finding little or no evidence of these antibodies in healthy, BSE-free cattle. In addition, highly elevated levels of autoantibodies to bovine brain components were found in the BSE cattle compared to BSE-free cattle. While the agent responsible for the production of these specific autoantibodies was unclear, it did appear that BSE cattle had been exposed to A. calcoaceticus. It was also noticed that the spongiform appearance is also characteristic of an autoimmune disease, known as experimental allergic encephalomyelitis (EIA), in which the immune system develops antibodies that attack and destroy specific brain components. EIA is an experimental model for multiple sclerosis. Since some antigens on the surface of A. calcoaceticus resemble brain tissues, it could be possible that infection with the bacterium causes the production of these autoantibodies that subsequently leads to BSE. While this study does not establish specific cause of BSE, according to the authors, it does support previous findings that autoantibodies to brain components are present in TSE's.

According to an article published in the journal Neurology (Neurology 1999;53:1907-1909,1937-1942), the risks of dementia and Alzheimer's disease are nearly doubled in older individuals with type-2 diabetes mellitus. These results were based on a 5-year population-based study in the Netherlands. In the study, baseline screening for diabetes and for dementia was performed in 6,370 persons aged 55 and older between 1990 and 1993. Overall, 10.9% of all those screened had type-2 diabetes. In the study, dementia developed in 126 individuals out of 5,232 nondemented participants observed for an average of 2 years. The relative risks of dementia and of Alzheimer's disease were both 1.9 among subjects with type-2 diabetes. The relative risk of dementia among the 10% of type 2 diabetics who were on insulin therapy was 4.3. It was hypothesized that the increased risk of dementia could be explained by either vascular disease or the nonvascular effects of diabetes. It was pointed out that both hyperglycemia and hypoglycemia are thought to have adverse effects on the brain.

Obtaining marketing approval for drugs and devices is one of the missions of TARGET HEALTH. The goal is to obtain a minimum of one NDA approval each year. Current NDA program projects include Cystic Fibrosis, COPD, Congestive Heart Failure, Infertility and Male and Female Sexual Dysfunction. An NDA was submitted and approved this year.

Familial adenomatous polyposis (FAP) is a rare genetic disorder where patients develop large numbers of intestinal polyps and, as a consequence, have a greatly increased risk of developing colon and rectal cancer at an early age. The FDA has approved Celebrex, a COX-2 inhibitor, as the first drug treatment aimed at reducing the number of intestinal polyps in patients with FAP. According to the FDA, Celebrex should be used only as an adjunct to usual care in managing FAP, which typically involves surgical removal of much or all of the lower intestine (colon and rectum) by early adulthood, with careful monitoring of any remaining lower intestinal tissue. Celebrex was granted accelerated approval for this new indication. Accelerated approval allows for early marketing of a product for treatment of a life-threatening condition for which no acceptable alternative treatments exist or which provides a meaningful therapeutic benefit over existing treatments based on a "surrogate" marker. The surrogate in this case was the number of polyps. The approval of Celebrex for FAP was based on a six-month placebo-controlled trial in 83 patients, sponsored, in part, by the NCI's Division of Cancer Prevention. In the study, there was a 28% reduction in the number of polyps in patients receiving 400 mg of Celebrex compared to 5% for those receiving placebo. The most common side effects were diarrhea and indigestion. The clinical benefit of reducing the number of colorectal polyps in FAP has not been demonstrated and it is also not known whether the effect of Celebrex treatment will persist after Celebrex is discontinued. Therefore, as a condition of approval, FDA is requiring further studies to evaluate clinical benefit, if any, of reducing polyps. Celebrex was approved in l998 for the relief of the signs and symptoms of rheumatoid and osteoarthritis. It is manufactured by SEARLE and co-marketed by PFIZER.

TARGET HEALTH excels in Regulatory Affairs and works closely with many of its clients and FDA. A pre-IND meeting is scheduled for the first week in October. 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 additional information, please contact Dr. Jules T. Mitchel at TARGET HEALTH.

The Prescription Drug User Fee Act of 1992 (the PDUFA), as amended by the Food and Drug Administration Modernization Act of 1997 (the FDAMA), authorizes FDA to collect user fees for certain marketing applications for drug and biological products, for establishments where the products are made and for each marketed product. Fees for applications for fiscal year (FY) 1999 were set by the FDAMA, subject to adjustment for inflation. Total application fee revenues fluctuate with the number of fee-paying applications FDA receives, and application fees are assessed at different rates for qualifying applications depending on whether the applications require clinical data on safety or effectiveness (other than bioavailability or bioequivalence studies). Applications that require clinical data are subject to the full application fee, while supplements that require clinical data and applications that do not require clinical data are assessed at one-half the standard fee. If FDA refuses to file an application or supplement, 75% of the application fee is refunded to the applicant. Since there was a drastic change in the number of applicants in1998 from previous years, the FDA has readjusted it formula for the calculation of user fees from a rolling average to a linear regression model. The new user fees will be as follows:

Applications requiring clinical data $272,282 Not requiring clinical data $136,141 Supplements requiring clinical data $136,141 Establishments $128,435 Products $ 18,364

TARGET HEALTH INC. is a full service CRO with full-time staff dedicated to all aspects of Regulatory Affairs, Clinical Research Management, Biostatistics, Data Management, Strategic Planning and Drug and Device Development. TARGET HEALTH also has a group of specialized advisors in the areas of Toxicology, Analytical Methods Validation, Product and Process Development, Quality Assurance, Manufacturing and Animal Health. Let us be of help to you on your next project

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Last modified: December 28, 1999