On Target

ON TARGET
COMPLIMENTARY NEWS LETTER OF TARGET HEALTH® INC.

16 September 2007

I. WHAT'S NEW?
Regulatory Affairs at Target Health
II. QUIZ - (Fill In The Blanks)
Long-Lasting Growth Hormone Developed
III. HISTORY OF MEDICINE
Forensic Medicine and the Origins of DNA Profiling
IV. METABOLISM -1
Is Actos, a Thiazolidinedione Antihyperglycemic, Antidiabetic Agent Safe Enough?
V. METABOLISM - 2
Is Avandia, a Thiazolidinedione Antihyperglycemic, Antidiabetic Agent Safe Enough?
VI. PUBLIC HEALTH
Smoking Ban In Scotland Has Far-Reaching Effects
VII. REGULATORY AFFAIRS
Guidance For Emergency Use Of Unapproved Medical Devices
VIII. TARGET HEALTH

I. WHAT'S NEW?

Regulatory Affairs at Target Health

On September 19, 2007, the Circulatory System Devices Panel will discuss, make recommendations and vote on a premarket approval application, sponsored by SyntheMed, Inc., for the REPEL-CV. REPEL-CV is a surgical adjuvant indicated for reducing the incidence, severity and extent of post-operative adhesion formation in patients undergoing cardiac surgery. Target Health is pleased to announce that it will attend the meeting on behalf of the sponsor. For this program, Target Health provided regulatory consulting, monitoring, data management, biostatistical and medical writing services. We prepared and submitted the PMA (including eCopy) and Target e*CRF® was used for the pivotal trial. The meeting is being held at the Hilton Washington DC North/Gaithersburg, Gaithersburg , MD.

For more information about Target Health, please contact Dr. Jules T. Mitchel. or Joyce Hays. Visit our Blog and Website.

II. QUIZ (Fill In The Blanks)

Long-Lasting Growth Hormone Developed

Researchers at the University of Sheffield in England, have developed a long-acting growth hormone. The new discovery could mean that children and adults with growth hormone 1) ___ will not have to have injections as often, reducing the need for daily treatments. Most hormones and 2) ___ have a short life and therefore require frequent injections as therapy. The new technology developed, means that scientists and clinicians are able to generate effective, long-acting hormones which promote growth over a minimum of ten days, after just one 3) ___. Cytokines are a subset of 4) ___ that enable communication between cells and the external environment, including the immune system. Cytokines hold huge potential for the treatment of disease due to their often fundamental roles in the development and progression of 5) ___. The research, published in the journal Nature Medicine, shows that the hormones are able to act for longer because of unique characteristics in the new 6) ___ created. Hormones normally circulate in blood attached to binding 7) ___ that prevent their clearance from the circulation and prolong their biological action. The new molecules, are able to bind to each other in a head-to-tail configuration, doubling their molecular mass in the 8) ___. This delays their absorption and elimination from the blood and therefore generates a hormone that will last for a longer period of time. This technology could bring significant benefit to patients. Children and adults with growth hormone deficiency have to give themselves daily injections and it is hoped that the new technology will reduce the number of times they have to do this to once every two weeks, or even once a month. The team is in the early stages of the drug 9) ___ process, and any drugs resulting from this research are several years away. The technology can also be applied to treat 10) ___ diseases such as multiple-sclerosis, cancer and metabolic diseases.

ANSWERS: 1) disorders; 2) cytokines; 3) injection; 4) hormones; 5) disease; 6) molecules; 7) proteins; 8) bloodstream; 9) development; 10) inflammatory

III. HISTORY OF MEDICINE

Forensic Medicine and the Origins of DNA Profiling

British geneticist Alec Jeffreys began working in 1977 on a technique that could identify individuals through samples of their DNA. In 1984, he and colleagues devised a way to use a newly discovered property of DNA, isolated areas of great variability between individuals called restriction fragment length polymorphisms (RFLP), for forensic identification—the original DNA fingerprint. In 1986, police asked Jeffreys for help in finding a man who had killed two girls. DNA tests exonerated the primary suspect. Through a genetic dragnet, police found the perpetrator, Colin Pitchfork, who gave himself away when he asked a friend for a substitute blood sample. Within a year, genetic fingerprinting was making the unique molecular structures of victims and suspects visible in criminal investigations around the world. Today, RFLP-based DNA analysis is being supplanted by newer techniques of genetic identification. Within a year, genetic fingerprinting was making the unique molecular structures of victims and suspects visible in criminal investigations around the world. Today, RFLP-based DNA analysis is being supplanted by newer techniques of genetic identification.

IV. METABOLISM - 1

Is Actos, a Thiazolidinedione Antihyperglycemic, Antidiabetic Agent Safe Enough?

Pioglitazone (Actos, Takeda) is a prescription drug of the class thiazolidinedione with hypoglycemic (antihyperglycemic, antidiabetic) action. Pioglitazone is widely used for glycemic control in patients with type 2 diabetes mellitus, but evidence is mixed regarding the influence of medications of this class on cardiovascular outcomes. As a result, a study published in the Journal of the American Medical Association (2007;298:1180-1188) was performed to systematically evaluate the effect of pioglitazone on ischemic cardiovascular events. For the study, a database containing individual patient-level time-to-event data collected during pioglitazone clinical trials was transferred from the drug's manufacturer for independent analysis. Trials were included if they were randomized, double-blinded, and controlled with placebo or active comparator. The primary outcome was a composite of death, myocardial infarction, or stroke. Secondary outcome measures included the incidence of serious heart failure. A fixed-effects approach was used to combine the estimates across the duration strata and statistical heterogeneity across all the trials was tested with the I2 statistic. For the study, a total of 19 trials were analyzed enrolling 16,390. Study drug treatment duration ranged from 4 months to 3.5 years. Results showed that the outcomes of death, myocardial infarction, or stroke occurred in 375 of 8554 patients (4.4%) receiving pioglitazone and 450 of 7836 patients (5.7%) receiving control therapy (P = .005). Progressive separation of time-to-event curves became apparent after approximately 1 year of therapy. Serious heart failure was reported in 200 (2.3%) of the pioglitazone-treated patients and 139 (1.8%) of the control patients (P = .002). The magnitude and direction of the favorable effect of pioglitazone on ischemic events and unfavorable effect on heart failure was homogeneous across trials of different durations, for different comparators, and for patients with or without established vascular disease. The authors concluded that pioglitazone is associated with a significantly lower risk of death, myocardial infarction, or stroke among a diverse population of patients with diabetes and that serious heart failure is increased by pioglitazone, although without an associated increase in mortality.

V. METABOLISM - 2

Is Avandia, a Thiazolidinedione Antihyperglycemic, Antidiabetic Agent Safe Enough?

Rosiglitazone (Avandia, GlaxoSmithKline) is a prescription drug of the class thiazolidinedione with hypoglycemic (antihyperglycemic, antidiabetic) action. Recent reports of serious adverse events with rosiglitazone use have raised questions about whether the evidence of harm justifies its use for treatment of type 2 diabetes. As a result, a study published in the Journal of the American Medical Association (2007;298:1189-1195) was performed to systematically review the long-term cardiovascular risks of rosiglitazone, including myocardial infarction, heart failure, and cardiovascular mortality. The data sources were MEDLINE, the GlaxoSmithKline clinical trials register, the US Food and Drug Administration Web site, and product information sheets for randomized controlled trials, systematic reviews, and meta-analyses published in English through May 2007. Studies were selected for inclusion if they were randomized controlled trials of rosiglitazone for prevention or treatment of type 2 diabetes, had at least 12 months of follow-up, and monitored cardiovascular adverse events and provided numerical data on all adverse events. For the study, a total of only 4 trials were included after detailed screening of 140 trials for cardiovascular events. The relative risks (RRs) of myocardial infarction, heart failure, and cardiovascular mortality were estimated using a fixed-effects meta-analysis of 4 randomized controlled trials (n = 14291, including 6421 receiving rosiglitazone and 7870 receiving control therapy, with a duration of follow-up of 1-4 years). Results showed that rosiglitazone significantly increased the risk of myocardial infarction (RR 1.42; P = .02) and heart failure (RR 2.09; P < .001) but without a significant increase in risk of cardiovascular mortality (RR 0.9). According to the authors, among patients with impaired glucose tolerance or type 2 diabetes, rosiglitazone use for at least 12 months is associated with a significantly increased risk of myocardial infarction and heart failure, but without a significantly increased risk of cardiovascular mortality.

VI. PUBLIC HEALTH

Smoking Ban In Scotland Has Far-Reaching Effects

Research showed that more than 13,000 people in Scotland died every year from the effects of smoking and within that number around 1,000 deaths could be attributed to passive smoking, known as environmental tobacco smoke (ETS) or second-hand smoke. In January 2004 the Scottish Executive published a tobacco control action plan, “A Breath of Fresh Air for Scotland: Improving Scotland’s Health – the Challenge.” The plan set out a range of measures to strengthen tobacco control, including prevention work, education and communications, controls on sales and the expansion of high quality cessation services. The Smoking, Health and Social Care (Scotland) Bill was introduced to Parliament on December 17, 2004, formally proposing that smoking should be banned in enclosed public places such as workplaces, pubs and restaurants. The Bill was approved on June 30, 2005, by a majority of 97 to 17 with one abstention. It received Royal Assent on August 5, 2005, and the new Act came into force on March 26, 2006. Now that the bill has passed, a prospective study, published in the British Medical Journal (2007;335:549-552), was performed to measure change in adult non-smokers' exposure to secondhand smoke in public and private places. Study participants included Scottish adults, aged 18 to 74 years. The study outcome measures include salivary cotinine (a metabolite of nicotine), self reported exposure to smoke in public and private places, and self reported smoking restriction in homes and in cars. Results showed that the geometric mean cotinine concentrations in adult non-smokers fell by 39%, from 0.43 ng/ml at baseline to 0.26 ng/ml after legislation (P<0.001). In non-smokers from non-smoking households, geometric mean cotinine concentrations fell by 49% (40% to 56%), from 0.35 ng/ml to 0.18 ng/ml (P<0.001). The 16% fall in cotinine concentrations in non-smokers from smoking households was not statistically significant. Reduction in exposure to secondhand smoke was associated with a reduction in reported exposure to secondhand smoke in public places (pubs, other workplaces, and public transport) but not in homes and cars. According to the authors, implementation of Scotland's smoke-free legislation has been accompanied within one year by a large reduction in exposure to secondhand smoke, which has been greatest in non-smokers living in non-smoking households. Non-smokers living in smoking households continue to have high levels of exposure to secondhand smoke.

VII. REGULATORY AFFAIRS

TARGET HEALTH excels in Regulatory Affairs and works closely with many of its clients performing 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.

Guidance For Emergency Use Of Unapproved Medical Devices

In an orderly developmental process, the developer of a device (a physician, scientist, or manufacturer) anticipates the need to conduct clinical studies and uses the IDE to ensure that adequate preclinical testing has been done, that the appropriate subjects will be selected, that subjects participate only after providing informed consent, that the device will be used properly, that subjects will be monitored adequately after the device is used, and that complete scientific data will be collected properly and promptly. These data then form the basis for subsequent marketing approval of the device. An emergency need to use an unapproved device may occur when an IDE for the device does not exist, when a physician wants to use the device in a way not approved under the IDE, or when a physician or institution is not approved under the IDE. FDA recognizes that even during the earliest phases of device design, development, and testing, emergencies arise where an unapproved device offers the only alternative for saving the life of a dying patient. Using its enforcement discretion, FDA will not object if a physician chooses to use an unapproved device in such an emergency, provided that the physician later justifies to FDA that an emergency actually existed. Each of the following conditions should exist for a situation to be considered an emergency:

the patient is in a life-threatening condition that needs immediate treatment;
no generally acceptable alternative for treating the patient is available; and
because of the immediate need to use the device, there is no time to use existing procedures to get FDA approval for the use.

FDA expects the physician to determine whether these criteria have been met, to assess the potential for benefits from the unapproved use of the device, and to have substantial reason to believe that benefits will exist. FDA further expects the physician not to conclude that an "emergency" situation exists in advance of the time when treatment may be needed based solely on the expectation that IDE approval procedures may require more time than remains. Physicians should be aware that FDA expects them to exercise reasonable foresight with respect to potential emergencies and to make appropriate arrangements under the IDE procedures far enough in advance to avoid creating a situation in which such arrangements are impracticable. In the event that a device is used in circumstances meeting the criteria listed above, FDA would expect the physician to follow as many patient protection procedures as possible. These include obtaining:

an independent assessment by an uninvolved physician;
informed consent from the patient or a legal representative;
institutional clearance as specified by institutional policies;
the IRB chairperson's concurrence; and
authorization from the sponsor, if an approved IDE for the device exists.

For more information about our expertise in Regulatory Affairs, please contact Dr. Jules T. Mitchel or Dr. Glen Park.

VIII. TARGET HEALTH

TARGET HEALTH INC. (www.targethealth.com)is a full service eCRO with full-time 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 Clinical Trial System, and Medical Writing. TARGET HEALTH's Pharmaceutical Advisory Dream Team 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

http://blog.targethealth.com
www.targethealth.com
Dr. Jules T. Mitchel, President
Ms Joyce Hays, CEO