On Target - Weekly Journal, Issue March 26, 2000

I	..	WHAT'S NEW
II		HISTORY OF MEDICINE Cataract Surgery
III		DRUG WITHDRAWALS Propulsid Rezulin
IV		DERMATOLOGY Non-Animal Skin Testing
V		ONCOLOGY Stomach Cancer and H. Pylori
VI		BASIC RESEARCH Drosophila Genome
VII		NEUROBIOLOGY Memory and Cortisol
VIII		FDA Freedom of Information Act (FOIA)
XI		TARGET HEALTH INC.

TARGET HEALTH is pleased to announce that Dr. Jules T. Mitchel will be attending the 4th Annual Orthopaedic Tissue Engineering Conference on April 13th and 14th at the Hilton Back Bay, Boston. Dr. Mitchel will be chairing the session on "Proactive Approaches to FDA Relations During Device Development to Insure Successful Development Programs." A Q&A session with Mr. Mark Citron (OSTEOTECH, Inc.) and Dr. Russ Pagano (CDRH, FDA) will follow the formal presentations. Dr. Mitchel will also be attending the American Urological Association Meeting in Atlanta (April 30- May 3). Please let us know if you will be attending any of these meetings or need additional information.

The earliest written reference to cataract surgery is found in Sanskrit manuscripts dating from the 5th century BCE. It is believed that these writings were by the Hindu surgeon Susruta who practiced a type of cataract surgery known as couching or reclination. In couching, cataractous lens are displaced away from the pupil to lie in the vitreous cavity in the back of the eye. This displacement of the lens enables the patient to see better. However, vision is still blurred because of the unavailability of corrective lenses. As recently as the middle of this century, couching was still practiced in Egypt, India, and Tibet. In the Western world, recent excavations in Babylonia (Iraq), Greece, and Egypt have uncovered bronze instruments that would have been appropriate for cataract surgery. The first written description of the cataract and its treatment in the West appears in 29 CE in De Medicinae, the work of the Latin encyclopedist Celsus. In it, Celsus describes in this work the practice of needling, or discission, of cataracts, a technique in which the cataract is broken up into smaller particles, thereby facilitating their absorption. Interestingly, Hippocrates does not refer to cataract surgery in his writings. Galen, the pivotal medical figure of antiquity whose theories went unchallenged for more than 1,500 years, erroneously believed that the lens rather than the retina was the seat of vision, and that its removal would cause blindness. History also records the use of bloodletting, antiphlogistics (agents to counteract inflammation and fever), and mercury to prevent or dissolve cataracts, all of which were unsuccessful.

Last week, Propulsid and Rezulin were withdrawn from the market. These withdrawals, while unfortunate from both the patient and business perspectives, show that the "system" is working. It is the opinion of TARGET HEALTH that no criticisms should be heaped on either the pharmaceutical industry or the FDA for initially approving these very useful drugs. Rather the FDA and Industry should be commended for their risk management approaches. TARGET HEALTH has developed an Internet-based Adverse Event Monitoring System (AEMS) to allow for the collection of safety signals, in real time, for both clinical trials and postmarketing surveillance. For more information, please contact Dr. Mitchel (julesmitchel@targethealth.com)

JANSSEN PHARMACEUTICALS announced that it will stop marketing cisapride (Propulsid) in the U.S. Propulsid was approved only for severe nighttime heartburn in patients with gastroesophageal reflux disease (GERD) who did not adequately respond to other therapies. According to the FDA, use of Propulsid was associated with 341 reports of heart rhythm abnormalities including 80 deaths. It should be noted, however, most of these events occurred in patients who were taking other medications or suffering from underlying conditions known to increase the risk of cardiac arrhythmia associated with Propulsid. Patients who are currently prescribed Propulsid have been urged to promptly contact their health care providers to discuss alternative treatments. JANSSEN will continue to make the drug available to patients who meet specific clinical eligibility criteria for a limited-access protocol.

Last week PARKE-DAVIS/WARNER-LAMBERT agreed with FDA's request to remove Rezulin (troglitazone) from the market. Rezulin was indicated for the treatment of type 2 diabetes mellitus. The FDA took this action after it reviewed recent safety data on Rezulin and two similar drugs, rosiglitazone (Avandia) and pioglitazone (Actos). Results showed that Rezulin was more toxic to the liver than the other two drugs. Data to date has shown that Avandia and Actos, both approved in the past year, offer the same benefits as Rezulin without the same risk. Severe liver toxicity has been known to occur with Rezulin since 1997. As with Propulsid, in consultation with FDA, PARKE-DAVIS strengthened the drug's labeling several times and has recommended close monitoring of liver function in patients taking Rezulin. After up to nine months of marketing experience with Avandia and Actos, it became clear that the newer drugs had less risk of severe liver toxicity. Patients using Rezulin should not discontinue taking Rezulin or other treatments for diabetes and have been urged to contact their physicians. Dr. Fred Reno (Toxicology), a charter member of TARGET HEALTH's Pharmaceutical Advisory Dream Team, was the lead toxicologist for one of the new drugs replacing Rezulin.

Psoriasis is mediated by T-lymphocytes, and CD11a/CD18 form subunits of lymphocyte function associated antigen (LFA-1). LFA-1 is a T-cell surface molecule important in T-cell activation, cytotoxic T-cell function, and T-cell adhesion to vascular endothelium and keratinocytes. According to an article published in the Journal of the American Academy of Dermatology (J Am Acad Dermatol 2000;42:428-435), a single infusion of humanized monoclonal antibody to CD11a, improves psoriasis for up to 10 weeks. The study evaluated the immunologic and clinical effects of single infusions of 0.03 mg/kg to 10.0 mg/kg humanized anti-CD11a monoclonal antibody (hu1124) in 31 patients with moderate to severe plaque psoriasis. Doses of hu1124 above 1.0 mg/kg (Group III) completely blocked blood levels of CD11a for more than 14 days in four of five patients and three of these patients experienced sustained complete blockade of CD11a on psoriatic lesional T cells. Patients who received doses between 0.3 mg/kg and 1.0 mg/kg (Group II) experienced lesser degrees and lower durations of blockade, both in peripheral blood and within psoriatic lesions. Doses below 0.3 mg/kg (Group I) produced only partial CD11a blockade in circulating T cells and no blockade in lesional T cells (by day 28). Epidermal thickness in the region of the plaques diminished in Groups II and III, but not in Group I. Similarly, psoriasis activity severity index (PASI) scores fell in Group II at Weeks 3 and 4 and in Group III at Weeks 2 through 10. Group I patients did not improve. Headache, fever, chills, and nausea were common adverse effects, but most abated within 24 hours of dosing.

The Environmental Protection Agency (EPA), the Occupational Safety and Health Administration (OSHA) and the Consumer Product Safety Commission (CPSC), have agreed to accept chemical safety data from a synthetic skin test in lieu of an animal test. This is the second substitute test to be approved after an ICCVAM (Interagency Coordinating Committee on the Validation of Alternative Methods) panel review. The first review resulted in the acceptance of a test called the Murine Local Lymph Node Assay that uses fewer animals to determine the potential of chemicals to cause allergic dermatitis. This is the first such general substitution of a non-animal test under a new federal program to reduce animal experimentation. The new, less painful assay also uses mice instead of guinea pigs. The new test, Corrositex, is sold as a test kit by INVITRO INTERNATIONAL of Irvine, Calif. In the test, a chemical or chemical mixture is placed on a collagen matrix barrier that serves as a kind of synthetic skin. Once it penetrates the barrier, the chemical causes a color change in a liquid detection system composed of indicator dyes that are sensitive to strong acids and bases at pH extremes. The time it takes for a test chemical to penetrate the barrier and produce a color change in the detection system is compared to a classification chart to determine corrosivity. The FDA also endorsed the acceptability of the method, but said that corrosivity testing for the types of products it regulates is likely to be limited. Since there are more than two thousand chemicals introduced each year, the substitution of Corrositex could save many laboratory animals in a year.

Stomach cancer is the second most common form of cancer. Helicobacter pylori bacteria can cause inflammation of the stomach tissue and cause blood flow to the infected area to increase, resulting in swelling and irritation. In about 10% of carriers, inflammation of the lower part of the stomach leads to ulcers. In a small percentage of H. pylori carriers, the inflammation can lead to cancer if, instead, the upper part of the stomach becomes inflamed, and acid secretion is reduced and the stomach's function impaired. Patients seem to get ulcers or cancer, but not both. According to an article published in the journal Nature, people who carry H. pylori in their stomachs are between 3 and 6 times more likely to develop stomach cancer and that this risk also depends on the genetic make-up of H. pylori's human host. In the study, 149 healthy relatives of stomach-cancer patients were studied in the west of Scotland and 393 stomach cancer patients in Warsaw, Poland. Subjects were tested for different forms of the IL-1- gene, and also for a gene for another interleukin, 'IL-1ra', which counteracts the effects of IL-1-. A variant of IL-1ra is known to be associated with a range of inflammatory problems. It was found that, among the relatives of cancer patients infected with H. pylori, the 45 with low levels of stomach acid were significantly more likely to carry one particular form of the IL-1- gene. Carriers of the inflammation-causing form of IL-1ra also produced less stomach acid. Likewise, the Polish study revealed that, for patients infected with H. pylori, the presence of both 'low acid' genes increased the risk of cancer by about 4-5 times. In all, 38% of stomach cancer cases can be attributed to these interleukin genes.

In Queens College, NYC, Dr. Mitchel was taught genetics by Dr. Donald Lancefield, the discoverer of Drosophila pseudobscura. We have all come a long way from counting vestigial and normal wings and seeing the flies fly away as the ether wore off, sometimes before the end of the experiments. TARGET HEALTH congratulates the major accomplishment described below.

According to an article published in the journal Science (Science: 2000;287:2185-2195,2218-2220), a substantially complete genome of the common fruit fly, Drosophila melanogaster, has been sequenced by CELERA GENOMICS. The Drosophila genome contains approximately 13,600 genes that encode a diverse group of molecules, including transcription and translation factors, cytochrome P450 monooxygenases, solute transporters and metabolic factors. Interestingly, the Drosophila genome contains many genes that are homologs for disease-associated genes in humans. In a related Science article, Drs. Thomas B. Kornberg and Mark A. Krasnow, of the University of California at San Francisco and Stanford University, respectively, remarked that the new Drosophila sequence may have yet another important use, as "the Rosetta stone for deciphering the human genome."

TARGET HEALTH is pleased to announce the completion of two major manuscripts in the area of depression is being sent to the FDA to support a new indication. The project was lead by Anita Islam, Ph.D. who holds a Ph.D. in Neurobiology from the City University of NY.

According to an article published in Nature Neuroscience (Nat Neurosci 2000; 3:313-314), elevated cortisol levels impair retrieval of long-term declarative memory but not overall cognitive function. According to the authors, the finding might mean that stress could have a negative impact on several situations when accurate memory is important, such as when a person is on a witness stand. In a double-blind randomized study, 36 healthy adults were asked to memorize 60 nouns that were displayed on a computer screen for 4 seconds each. In a free-recall test, participants wrote down as many of the words as they could remember. In a test of their ability to recognize the words, participants had to pick out the original words from a larger list. Participants received cortisone tablets (25 mg) or placebo at various times during the tests. One hour after treatment with cortisone, salivary concentrations of cortisol were comparable to levels caused by major stress. When cortisone was given 1 hour prior to the free-recall test, it significantly impaired recall performance as compared with placebo treatment on tests given 2 weeks apart to the same individuals. However, cortisone did not affect confabulative errors or recognition memory.

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.

In fiscal year (FY) 1999, FDA's Office of Regulatory Affairs (ORA) and Office of Criminal Investigation (OCI) reported an all-time-high number of recalls and detentions of potentially hazardous products; carried out an unprecedented total of arrests and criminal convictions; and saw the successful conclusion of court cases resulting in record FDA-requested payments in the industry. Last year, non-compliant blood and blood products accounted for nearly one-third (1,295) of the total 3,736 recalls. The second highest number of recalls (1,263) included medical devices. The FY 1999 total of product recalls was almost 30% above the average over the past 10 years. Detentions of food and medical devices also accounted for the great majority of the 41,474 import shipments of violative and unsafe products. Almost one-half (19,283) of these shipments contained fresh produce and other food regulated by FDA's Center for Food Safety and Applied Nutrition (CFSAN). CDRH-regulated products accounted for nearly one-third (13,353) of the total. ORA issued 7,303 lists of observations noting noncompliance with public health regulations and 900 warning letters, and initiated 25 seizures and eight injunctions. One FDA injunction, based on repeated findings of non-compliance in such critical areas as process validation and production and process control, resulted in a consent degree in which a firm agreed to stop manufacturing and distributing many of its products until it corrects its manufacturing problems. The firm also agreed to pay $100 million to the U.S. Treasury, the highest sum ever paid by an FDA-regulated company for a civil violation of public health laws. Investigators from FDA's OCI last fiscal year arrested 373 suspected violators of public health laws and won 211 court convictions, the highest totals since the office was created seven years ago. Several criminal convictions resulting from OCI's investigations included heavy fines and lengthy incarcerations. The most prominent of these cases involved massive marketing of Protropin. This synthetic human growth hormone had been approved by FDA on condition that its sponsor conduct a post-marketing study of 300 children who failed to reach the minimum height appropriate for their age. In spite of this agreement, the sponsor aggressively promoted the pediatric drug for unapproved medical conditions, and manipulated internal documents to conceal illegal practices that boosted the sales of Protropin to more than $1 billion. Last May, the sentencing resulted in the payment of a $30 million criminal fine and $20 million in restitution, the largest FDA criminal penalty against a pharmaceutical company.

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.

Send mail to webmaster@targethealth.com with questions or comments about this web site.
Copyright � 1997-1999 Target Health Inc.
Last modified: March 28, 2000