18 November 2007
I. WHAT'S NEW?
Another Successful Pivotal Trial Used Target e*CRF®
II. QUIZ - (Fill In The Blanks)
Ancient Retrovirus Is Resurrected
III. HISTORY OF MEDICINE
Evolutionary Biology and the Human Genome as a Fossil Record
IV. PSYCHIATRY
There is a Lag in Brain Development in ADHD
V. METABOLISM
Treatment of Glucocorticoid-Induced Osteoporosis
VI. OPHTHALMOLOGY
Fenofibrate Works In Diabetic Retinopathy - Not Related to Lipid Reduction
VII.
REGULATORY AFFAIRS
FDA Revamping Advisory Meeting Process
VIII. TARGET HEALTH
II. QUIZ
(Fill
In The Blanks)
Ancient Retrovirus Is Resurrected
Retroviruses have been around longer than humanity itself. The best-known family member, 1) ___, is a relative youngster, with its first known human infections occurring sometime in the mid-20th century. But although many retroviruses went extinct hundreds of thousands or millions of years ago, researchers studying the pathogens don’t use the traditional tools of paleontologists. They need look only as far as our own 2) ___. Retroviruses infect cells and replicate by inserting their DNA into their host cell’s genome. If that cell happens to be a germ cell, such as a sperm, an egg or their precursors, then the retroviral DNA is 3) ___ by offspring just like a normal gene. Humans have many defunct retroviruses deposited in our DNA, remnants of ancient 4) ___ that replicated in our ancestors millions of years ago. Now, researchers have brought one of those retroviruses back to life. In our DNA, there’s a 5) ___ record of retroviruses that used to infect us. In fact, about 8% of human DNA is made up of retroviral 6) ___. Researchers have excavated some of that DNA and, in an attempt to better understand how humans and retroviruses co-evolved, they have resurrected an ancient retrovirus, one that can create new viral 7) ___ and infect human cells. They describe their work in a paper published by PLoS Pathogens last month. The extinct retroviruses embedded in our DNA can’t reproduce because of mutations in one or more of their genes. The younger of these human endogenous retroviruses (or HERVs) have fewer changes, and judging by the paucity of genetic alterations, at least one subfamily, HERV-K, was likely still active less than a few hundred thousand years ago. Different members of this subfamily have slightly different mutations. As of a few months ago, there was no replication-competent form of this virus. To eliminate those 8) ___ that kept HERV-K from replicating, researchers deduced a genetic sequence that was a consensus of 10 different HERV-K proviruses and synthesized the whole viral genome from scratch. Then, they took that sequence (which they dubbed HERV-KCON) and inserted it into cultured human 9) ___ to see if it would result in the creation of HERV-K structural proteins. Their consensus sequence resulted in not only functional proteins, but in a retrovirus that was capable of creating new viral particles and integrating itself into a host cell’s 10) ___. This is the 11) ___ time this has been done with a viral genome that was effectively dead, and now is alive — or at least has all the functions that suggest it should replicate. This project, at Rockefeller University, began, because certain human and non-human primate cells produce proteins that appear to block HIV from replicating. And the question is, where did the proteins come from? By studying these extremely old viruses, we can tap into what happened in our ancestors millions and millions of years ago.IV. PSYCHIATRY
There is a Lag in Brain Development in ADHD
According to an article published in the online edition of the Proceedings of the National Academy of Sciences (12 November 2007), while the human brain matures in a normal pattern in children with attention deficit hyperactivity disorder (ADHD), it is delayed three years in some regions. The delay in ADHD was most prominent in regions at the front of the brain's outer mantle (cortex), important for the ability to control thinking, attention and planning. Otherwise, both groups showed a similar back-to-front wave of brain maturation with different areas peaking in thickness at different times. Previous brain imaging studies failed to detect the developmental lag because they focused on the size of the relatively large lobes of the brain. Results of the current study showed that among 223 youth with ADHD, half of 40,000 cortex sites attained peak thickness at an average age of 10.5, compared to age 7.5 in a matched group of youth without the disorder. For the study, participants ranging from preschoolers to young adults, were scanned at least twice at about three-year intervals. Preschoolers and young adults were studied since, during this age range, the cortex thickening observed during childhood gives way to thinning following puberty, as unused neural connections are pruned for optimal efficiency during the teen years. In both ADHD and control groups, sensory processing and motor control areas at the back and top of the brain peaked in thickness earlier in childhood, while the frontal cortex areas responsible for higher-order executive control functions peaked later, during the teen years. These frontal areas support the ability to suppress inappropriate actions and thoughts, focus attention, remember things from moment to moment, work for reward, and control movement - functions often disturbed in people with ADHD. Circuitry in the frontal and temporal (at the side of the brain) areas that integrate information from the sensory areas with the higher-order functions showed the greatest maturational delay in youth with ADHD. For example, one of the last areas to mature, the middle of the prefrontal cortex, lagged five years in those with the disorder. The motor cortex emerged as the only area that matured faster than normal in the youth with ADHD, in contrast to the late-maturing frontal cortex areas that direct it. This mismatch might account for the restlessness and fidgety symptoms common among those with the disorder, the researchers suggested. The authors noted that the delayed pattern of maturation observed in ADHD is the opposite of that seen in other developmental brain disorders like autism, in which the volume of brain structures peak at a much earlier-than-normal age.V. METABOLISM
Treatment of Glucocorticoid-Induced Osteoporosis
Bisphosphonate therapy is the current standard of care for the prevention and treatment of glucocorticoid-induced osteoporosis. However, studies are lacking of anabolic therapy in patients who are receiving long-term glucocorticoids and who are at high risk for fracture. As a result, a study published in the New England of Medicine (2007;357:2028-2039), compared teriparatide (Forteo, Eli Lilly) with alendronate in 428 women and men with osteoporosis (ages, 22 to 89 years) who had received glucocorticoids for at least 3 months (prednisone equivalent, 5 mg daily or more). The investigation was an 18-month randomized, double-blind, controlled trial including 214 patients who received 20 µg of teriparatide once daily, and 214 received 10 mg of alendronate once daily. The primary outcome was the change in bone mineral density at the lumbar spine. Secondary outcomes included changes in bone mineral density at the total hip and in markers of bone turnover, the time to changes in bone mineral density, the incidence of fractures, and safety. Results showed that at the last measurement, the average bone mineral density at the lumbar spine had increased more in the teriparatide group than in the alendronate group (7.2% vs. 3.4%, P<0.001). A significant difference between the groups was reached by 6 months (P<0.001). At 12 months, bone mineral density at the total hip had increased more in the teriparatide group. Fewer new vertebral fractures occurred in the teriparatide group than in the alendronate group (0.6% vs. 6.1%, P=0.004), while the incidence of nonvertebral fractures was similar in the two groups (5.6% vs. 3.7%, P=0.36). Significantly more patients in the teriparatide group had at least one elevated measure of serum calcium. It was concluded that among patients with osteoporosis who were at high risk for fracture, bone mineral density increased more in patients receiving teriparatide than in those receiving alendronate.VI. OPHTHALMOLOGY
Fenofibrate Works In Diabetic Retinopathy - Not Related to Lipid Reduction
Laser treatment for diabetic retinopathy is often associated with visual field reduction and other ocular side-effects. As a result, a study published in The Lancet (2007;370:1687-1697), was performed to assess whether long-term lipid-lowering therapy with fenofibrate could reduce the progression of retinopathy and the need for laser treatment in patients with type 2 diabetes mellitus. The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study was a multinational randomized trial of 9,795 patients aged 50–75 years with type 2 diabetes mellitus. Eligible patients were randomly assigned to receive fenofibrate 200 mg/day (n=4,895) or matching placebo (n=4,900). At each clinic visit, information concerning laser treatment for diabetic retinopathy, a prespecified tertiary endpoint of the main study, was gathered. Adjudication by ophthalmologists masked to treatment allocation, defined instances of laser treatment for macular oedema, proliferative retinopathy, or other eye conditions. In a substudy of 1,012 patients, standardized retinal photography was done and photographs graded with Early Treatment Diabetic Retinopathy Study (ETDRS) criteria to determine the cumulative incidence of diabetic retinopathy and its component lesions. Results showed that laser treatment was needed more frequently in participants with poorer glycemic or blood pressure control than in those with good control of these factors, and in those with a greater burden of clinical microvascular disease. Interestingly, the need for laser treatment was not affected by plasma lipid concentrations. The requirement for first laser treatment for all retinopathy was significantly lower in the fenofibrate group than in the placebo group (3•4% vs 4•9%; p=0•0002). In the ophthalmology substudy, the primary endpoint of 2-step progression of retinopathy grade did not differ significantly between the two groups. By contrast, in patients with pre-existing retinopathy, significantly fewer patients on fenofibrate had a 2-step progression than did those on placebo (3.1% vs 14•6; p=0•004). An exploratory composite endpoint of 2-step progression of retinopathy grade, macular oedema, or laser treatments was significantly lower in the fenofibrate group than in the placebo group (p=0•022). According to the authors, treatment with fenofibrate in individuals with type 2 diabetes mellitus reduces the need for laser treatment for diabetic retinopathy, although the mechanism of this effect does not seem to be related to plasma concentrations of lipids.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.FDA Revamping Advisory Meeting Process
So far this year the agency has convened 47 meetings of expert independent advisory committees to advise FDA on topics such as new gene therapies and the safety of children’s cough and cold medicines. The FDA has just announced several steps to strengthen its advisory committee processes in ways consistent with recommendations of the Institute of Medicine. The measures include proposed new guidance or procedures on advisory committee voting, on disclosing information on conflicts of interest, and on security and appropriate conduct for participants at meetings. Other improvements include greater clarity to FDA’s advisory committee Web site. A draft guidance document recommends that advisory committees adhere to a process of simultaneous voting, in which all members vote at once. The results of the vote would be announced immediately. How each member voted would be part of the public record. A second draft guidance issued recently lays out recommended changes to the process of public disclosure of financial interests that create conflicts of interest for advisory committee members. The draft guidance makes the process more transparent and consistent by having all advisory committee members publicly disclose interests for which a waiver is granted. The draft guidance also includes redesigned disclosure and waiver templates that are clearer and easier for the general public to understand. In addition, FDA has improved its Web page on advisory committees by providing better access to information about waivers granted for conflicts of interest. This Web page provides current information about upcoming advisory committee meetings and other updated information related to FDA's advisory committee processes. Finally, the FDA has recently posted the names of outside experts that it has named to a new risk communication advisory committee to make recommendations to FDA about how best to communicate the risks and benefits of FDA regulated products. FDA’s policies on advisory committees continue to be informed by new studies on conflicts of interest. The agency asked a consultant, Eastern Research Group, to study 16 recent advisory committees. The report highlights the difficulty of assembling highly qualified experts who are free of conflicts and finds that those who have received waivers appear to be significantly more qualified than those who have not received waivers.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
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