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12 June 2006

I.  WHAT'S NEW?
   Experience in Regulatory Affairs
II.  QUIZ (Fill  In The Blanks)
   Global Warming – Poison Ivy: Faster Growth, With Bigger & More Toxic Plants
III.  HISTORY OF MEDICINE
   Guy Maupassant (1850-1893)
IV. PUBLIC HEALTH
   New Vaccine Approved For HPV Infection Prevention
V. HIV/AIDS
   Vaccine Effectiveness in the Monkey
VI. NEONATOLOGY
   Risks Associated ACE Inhibitors in First Trimester of Pregnancy
VII. INFECTIOUS DISEASE
   How Long Should We Treat With Antibiotics?
VIII. FDA
   Getting Products To The Market Faster
IX. Target Health Inc.

I. WHAT'S NEW

Experience in Regulatory Affairs

Target Health is pleased to announce that it is managing the following FDA meetings this Spring, Summer and Fall:

Pre-IND:  Idiopathic Parkinson's Disease, Dental Caries, Osteoporosis, Fibromyalgia Syndrome and Traumatic Brain Injury
Pre-NDA:  Topical Infectious Disease, Hereditary Angioedema and Cystic Fibrosis

Please visit us at Booth 1956 at the DIA Annual Meeting in Philadelphia. Dr. Mitchel will also be giving a talk on Tuesday at 10:30 on Data Standards and Web Trials. Please let us know if you will be attending and learn more about our Asian Clinical Trial Network.  For more information, please contact  Dr. Jules T. Mitchel.

II. QUIZ (Fill  In The Blanks)

Global Warming – Poison Ivy: Faster Growth, With Bigger & More Toxic Plants 

An irritating consequence of 1) ___ warming could be a dramatic increase in the amount of poison ivy and its ability to cause 2) ___ reactions. A six-year study, appearing in the Proceedings of the National Academy of Sciences (June 1, 2006), shows that elevated atmospheric carbon dioxide in an intact forest ecosystem increases photosynthesis, water use efficiency, growth and biomass of poison ivy. It makes the forest a more dangerous place – backyards too. Poison Ivy is a remarkable plant. It can grow just about anywhere. About 3) __% of people develop an allergic reaction to poison ivy that includes an itchy rash and blisters, caused by skin contact with the oily sap--or 4) __--of the plant. As the virulence of the plant increases due to global warming from increased atmospheric carbon dioxide, even more people will be effected. With carbon dioxide levels 5) ___, the plant's growth rate and virulence are already on the rise. Poison ivy plants exposed to elevated CO2 levels averaged 149% faster growth compared with 6) ___ plants; and the lind of poison they make becomes more poisonous. This Poison Ivy study is among the first to link increased growth and 7) ___ with rising levels of CO2, which in turn is causing global warming. Other experts predict future medical problems from more toxic plants. This important research is yet another reason to be concerned about mankind's steadily increasing production of carbon dioxide through the burning of 8) ___ fuels. These experiments predict that poison ivy will become more abundant, resulting in more exposures to these dangerous plants, and at the same degree of exposure it is likely to cause worse skin reactions than currently seen. This is worrisome because of the intense skin reactions that these plants already commonly produce in the majority of the exposed population.

Answers: 1) global; 2) allergic; 3) 80%; 4) resin; 5) increasing; 6) control; 7) toxicity; 8) fossil   

III. HISTORY OF MEDICINE

Guy de Maupassant (1850-1893) 

Guy de Maupassant (1850-1893) excelled as a realist writer of the 19th century, with fantastical short stories being an outstanding example of his literary genius. In his masterpiece "Le Horla," nightmares, sleep paralysis, a hemianopic (one eye blind) pattern of loss and recovery of vision, and palinopsia (visual after image) are found. In "Qui sait" and in "La main" there is also an illusory movement of the objects in the visual field, although in a dreamlike complex pattern. In "Lui," autoscopy (a person while believing to be awake sees her/his body and the world from a location outside her/his physical body) and hypnagogic (vivid dream-like auditory, visual, or tactile hallucinations) emerge as fantastical key elements. Maupassant suffered from severe migraine and neurosyphilis involving the optic nerve, which led to his death by general paralysis of the insane. Visual loss and visual hallucinations affected the author in his last years, before a delirant state confined him to a nursing home.

IV. PUBLIC HEALTH

New Vaccine Approved For HPV Infection Prevention

The FDA announced the approval of Gardasil, the first vaccine developed to prevent cervical cancer, precancerous genital lesions and genital warts due to human papillomavirus (HPV) types 6, 11, 16 and 18. The vaccine is approved for use in females 9-26 years of age. Gardasil was evaluated and approved in six months under FDA's priority review process, a process for products with potential to provide significant health benefits. HPV is the most common STD infection in the United States. The Centers for Disease Control and Prevention estimates that about 6.2 million Americans become infected with genital HPV each year and that over half of all men and women become infected at some time in their lives. On average, there are 9,710 new cases of cervical cancer and 3,700 deaths attributed to it in the US each year. Worldwide, cervical cancer is the second most common cancer in women; and is estimated to cause over 470,000 new cases and 233,000 deaths each year. For most women, the body's own defense system will clear the virus and infected women do not develop related health problems. However, some HPV types can cause abnormal cells on the lining of the cervix that years later can turn into cancer. Other HPV types can cause genital warts. Gardasil is a recombinant vaccine (contains no live virus) that is given as three injections over a six-month period. Immunization with Gardasil is expected to prevent most cases of cervical cancer due to HPV types included in the vaccine. However, females are not protected if they have been infected with that HPV type(s) prior to vaccination, indicating the importance of immunization before potential exposure to the virus. Also, Gardasil does not protect against less common HPV types not included in the vaccine, thus routine and regular pap screening remain critically important to detect precancerous changes in the cervix to allow treatment before cervical cancer develops. Four studies, one in the US and three multinational, were conducted in 21,000 women to show how well Gardasil worked in women between the ages of 16 and 26 by giving them either the vaccine or placebo. The results showed that in women who had not already been infected, Gardasil was nearly 100% effective in preventing precancerous cervical lesions, precancerous vaginal and vulvar lesions, and genital warts caused by infection with the HPV types against which the vaccine is directed. While the study period was not long enough for cervical cancer to develop, the prevention of these cervical precancerous lesions is believed highly likely to result in the prevention of those cancers. Two studies were also performed to measure the immune response to the vaccine among younger females aged 9-15 years. Their immune response was as good as that found in 16-26 year olds, indicating that the vaccine should have similar effectiveness when used in the 9-15 year age group. The safety of the vaccine was evaluated in approximately 11,000 individuals. Most adverse experiences in study participants who received Gardasil included mild or moderate local reactions, such as pain or tenderness at the site of injection. Merck, the manufacturer of the vaccine, has agreed to conduct several studies following licensure, including additional studies to further evaluate general safety and long-term effectiveness. The manufacturer will also monitor the pregnancy outcomes of women who receive Gardasil while unknowingly pregnant.  Also, the manufacturer has an ongoing study to evaluate the safety and effectiveness of Gardasil in males.

V. INFECTIOUS DISEASE

Vaccine Effectiveness in HIV/AIDS   

In 2005, more than 11,000 people became infected with HIV every day. If that rate continues unchecked, the virus could infect another 40 million people during the coming decade. Results of two new studies suggest that even if an HIV vaccine offers imperfect protection against the virus, it might provide vaccinated individuals with an important benefit: a significant survival advantage after infection. Such a survival advantage was observed in two monkey studies published online in Science (DOI: 10.1126/science.1124226; 2006) and in the Journal of Experimental Medicine (DOI: 10.1084/jem.20060657; 2006). Study results showed that monkeys vaccinated against simian immunodeficiency virus (SIV), a close relative of HIV that causes an AIDS-like disease in monkeys, and then exposed to the virus, survived significantly longer than unvaccinated animals exposed to SIV. The studies also identified a measurable marker of SIV vaccine effectiveness in monkeys, something known as an immune correlate of vaccine efficacy. Further study is needed to determine if the immune correlate could predict the effectiveness of a vaccine against HIV in humans. The SIV vaccine regimen used in the two studies was a simplified version of a preventive human HIV vaccine strategy and is currently undergoing Phase II human clinical trials in the US, the Caribbean and sub-Saharan Africa. This vaccine regimen has two parts: a primer vaccine consisting of noninfectious HIV DNA; and a booster vaccine made from several HIV proteins delivered in a harmless adenovirus vector. Current plans call for testing the efficacy of the vaccine regimen in large-scale human clinical trials some time next year. To examine the theory that some imperfect HIV vaccines may still allow infected people to live longer and healthier lives, the study design sought to determine if SIV vaccines confer such a survival advantage to monkeys. Results showed that the best way to predict survival after a vaccinated monkey is infected with SIV is by measuring, early in infection, levels of a specific subset of immuneT cells known as the memory CD4+ T cells. Memory CD4+ T cells are T cells that have been activated by bacteria and viruses upon first exposure and are primed to act more quickly upon reinfection. Of the approximately one trillion T cells in the average adult, more than half are memory cells. Normally, a rapid and significant loss of these memory CD4+ T cells occurs early on in SIV infection: about ten days into the infection, when the levels of virus in the bloodstream are at their peak, up to 80% of the memory CD4+ T cells in some tissues became infected, and ultimately, nearly all of those memory CD4+ T cells are lost. However, vaccinating the monkeys can lessen this damage to the immune system. In the study, of six vaccinated monkeys and six unvaccinated monkeys exposed to SIV, the vaccinated group had about 3 to 5 times fewer memory CD4+ T cells infected and destroyed. According to the authors, if the virus wipes out only a fraction of the memory CD4+ T cells that it might otherwise destroy, that should allow the animals to live longer. Likewise, if HIV vaccines can prevent the destruction of these memory cells in humans, it may be possible to provide people with longer, healthier lives.

VI.  NEONATOLOGY

Risks Associated ACE Inhibitors in First Trimester of Pregnancy 

Use of angiotensin-converting–enzyme (ACE) inhibitors during the second and third trimesters of pregnancy is contraindicated because of their association with an increased risk of fetopathy. In contrast, first-trimester use of ACE inhibitors has not been linked to adverse fetal outcomes. As a result, a study published in the New England Journal of Medicine (2006;354:2443-2451) was performed to assess the association between exposure to ACE inhibitors during the first trimester of pregnancy only and the risk of congenital malformations. To test this hypothesis, a cohort of 29,507 infants were studied who has enrolled in Tennessee Medicaid and born between 1985 and 2000, and for whom there was no evidence of maternal diabetes. Results showed that there were 209 infants with exposure to ACE inhibitors in the first trimester alone, 202 infants with exposure to other antihypertensive medications in the first trimester alone, and 29,096 infants with no exposure to antihypertensive drugs at any time during gestation. Major congenital malformations were identified from linked vital records and hospitalization claims during the first year of life and confirmed by review of medical records. Infants with only first-trimester exposure to ACE inhibitors had an increased risk of major congenital malformations (risk ratio [RR], 2.71) as compared with infants who had no exposure to antihypertensive medications. In contrast, fetal exposure to other antihypertensive medications during only the first trimester did not confer an increased risk (RR, 0.66). Infants exposed to ACE inhibitors were at increased risk for malformations of the cardiovascular system (RR, 3.72) and the central nervous system (RR, 4.39). According to the authors, exposure to ACE inhibitors during the first trimester cannot be considered safe and should be avoided.

VII. INFECTIOUS DISEASE

How Long Should We Treat With Antibiotics? 

A study, recently published in the British Medical Journal (2006; 332:1355–1358), was performed to compare the effectiveness of discontinuing treatment with amoxicillin after three days or eight days in adults admitted to hospital with mild to moderate-severe community acquired pneumonia, who were substantially improved after an initial three days' treatment. The study was a randomized, double blind, placebo controlled non-inferiority trial performed in 9 secondary and tertiary care hospitals in the Netherlands. Study participants included adults with mild to moderate-severe community acquired pneumonia (pneumonia severity index score  110). For the study, patients who had substantially improved after three days' treatment with intravenous amoxicillin were randomly assigned to oral amoxicillin (n = 63) or placebo (n = 56) three times daily for five days. The primary outcome measure was the clinical success rate at day 10. Secondary outcome measures were the clinical success rate at day 28, symptom resolution, radiological success rates at days 10 and 28, and adverse events.
Results showed that baseline characteristics were comparable, with the exception of symptom severity, which was worse in the three day treatment group. In the three day and eight day treatment groups the clinical success rate at day 10 was 93% for both (difference 0.1%) and at day 28 was 90% compared with 88% (difference 2.0%). Both groups had similar resolution of symptoms. Radiological success rates were 86% compared with 83% at day 10 (difference 3%) and 86% compared with 79% at day 28 (difference 6%). Six patients (11%) in the placebo group and 13 patients (21%) in the active treatment group reported adverse events (P = 0.1). According to the authors, discontinuing amoxicillin treatment after three days is not inferior to discontinuing it after eight days in adults admitted to hospital with mild to moderate-severe community acquired pneumonia who substantially improved after an initial three days' treatment.

VIII. FDA

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.

Getting Products To The Market Faster

Fast Track refers to a process for interacting with FDA during drug development. Priority Review applies to the time frame the FDA targets for reviewing a completed application. Accelerated Approval (Subpart H) applies to the design and content of the studies used to support a marketing claim. Fast Track is a formal mechanism to interact with the FDA using approaches that are available to all applicants for marketing claims. The Fast Track mechanism is described in the Food and Drug Administration Modernization Act of 1997 (FDAMA). The benefits of Fast Track include scheduled meetings to seek FDA input into development plans, the option of submitting a New Drug Application in sections rather than all components simultaneously, and the option of requesting evaluation of studies using surrogate endpoints (see Accelerated Approval below). The Fast Track designation is intended for the combination of a product and a claim that addresses an unmet medical need, but is independent of Priority Review and Accelerated Approval. An applicant may use any or all of the components of Fast Track without the formal designation. Fast Track designation does not necessarily lead to a Priority Review or Accelerated Approval. An FDA Guidance on Fast Track Designation provides more detail with a citation of the relevant portion of the statue. Priority Review is a designation for an application after it has been submitted to the FDA for review for approval of a marketing claim. Under the Food and Drug Administration Modernization Act (FDAMA), reviews for New Drug Applications are designated as either Standard or Priority. A Standard designation sets the target date for completing all aspects of a review and the FDA taking an action on the application (approve or not approve) at 10 months after the date it was filed. A Priority designation sets the target date for the FDA action at 6 months. A Priority designation is intended for those products that address unmet medical needs. Internal FDA procedures for the designation and responsibilities for a Priority Review are detailed in the Manual of Policies and Procedures. Accelerated Approval or Subpart H Approval is a program described in the NDA regulations that is intended to make promising products for life threatening diseases available on the market on the basis of preliminary evidence prior to formal demonstration of patient benefit. The studies are designed to measure and the FDA evaluation is performed on the basis of a surrogate marker (a measurement intended to substitute for the clinical measurement of interest, usually prolongation of survival) that is considered likely to predict patient benefit. The approval that is granted may be considered a provisional approval with a written commitment to complete clinical studies that formally demonstrate patient benefit. Absent a formal demonstration of patient benefit, a risk benefit assessment cannot be made. Accelerated Approval designation does not necessarily lead to a Priority Review.

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

IX. TARGET HEALTH

TARGET HEALTH INC. (www.targethealth.com) is a full service e*CRO 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 (PADT) assists companies in strategic planning from Discovery to Market Launch. Let us help you on your next project.

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