Science Weekly Extra: The big bang at the LHC

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Lyn Evans relives the moment he found out something had gone horribly wrong with the LHC

Science Weekly: Do politicians only hear the advice they want to hear?

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The sacking of David Nutt; fading hopes for the Copenhagen climate talks; and the moment the LHC broke down

AUGMENT Approved in Canada – Target e*CRF® Has It’s 18th EDC Regulatory Approval 

Target e*CRF® has now been used in the approval of 5 drugs, 1 biologic, 3 devices, and 9 diagnostic devices in the US, Canada, Europe and Asia. Indications include prostate cancer, infertility, autoinflammatory diseases, head lice, emergency contraception, periodontal disease, orthopedics, cardiac surgery, and multiple diagnostics including cardiac biomarkers, hepatitis and infectious diseases. Since 1993, there are 30 products for which Target Health has played a major role in the development and approval processes. That translates to about 2 approvals per year. Pretty good track record for a company that currently has 44 employees. There were 3 approvals this year. Next year, 2 approvals are expected from FDA and 1 from the EMEA. 

On 3 November 2009, BioMimetic Therapeutics, Inc. announced that it has received approval from Health Canada to begin the marketing of its lead orthopedic product, AugmentTM Bone Graft, as an alternative to the use of autograft in midfoot, hindfoot and ankle fusion indications. Augment is a completely synthetic grafting system for bone regeneration and is composed of a purified recombinant growth factor, recombinant human platelet derived growth factor (rhPDGF-BB), and a synthetic calcium phosphate matrix, beta-tricalcium phosphate (�-TCP). The rhPDGF-BB provides the biological stimulus for tissue repair by stimulating the recruitment and proliferation of new bone forming cells and blood vessels, while the �-TCP provides the framework or scaffold for new bone growth to occur. Augment is the Company’s second product to receive marketing approval in Canada. GEM 21S®, a grafting material for bone and periodontal regeneration, was approved for use by the FDA and Health Canada in 2005 and 2006, respectively. Health Canada approval of Augment was based on results from a three center, 60 patient open label trial in which all individuals were treated with Augment. Patients were studied for nine months following implantation of the product and were assessed for healing using clinical and radiographic endpoints. 

For more information about Target Health and our software tools for paperless clinical trials, please contact Dr. Jules T. Mitchel (212-681-2100 ext 0) or Ms. Joyce Hays (joycehays@targethealth.com). Target Health’s software tools are designed to partner with both CROs and Sponsors. Please visit the Target Health Website: www.targethealth.com

Sleep Loss Linked to Increase in Alzheimer’s Plaques

Chronic sleep deprivation in a mouse model of Alzheimer’s disease makes Alzheimer’s brain 1) ___ appear earlier and more often, researchers at Washington University School of Medicine in St. Louis report online this week in Science Express. They also found that orexin, a protein that helps regulate the sleep cycle, appears to be directly involved in the increase. Neurodegenerative disorders like Alzheimer’s disease and Parkinson’s disease often disrupt 2) ___. The new findings are some of the first indications that sleep loss could play a role in the genesis of such disorders. “Orexin or compounds it interacts with may become new drug targets for treatment of Alzheimer’s disease,” says senior author David M. Holtzman, M.D., the Andrew and Gretchen Jones Professor and chair of the Department of Neurology at the School of Medicine and neurologist-in-chief at Barnes-Jewish Hospital. “The results also suggest that we may need to prioritize treating sleep disorders not only for their many acute effects but also for potential long-term impacts on 3) ___ health.” Holtzman’s laboratory uses a technique called in vivo microdialysis to monitor levels of amyloid beta in the brains of mice genetically 4) ___ as a model of Alzheimer’s disease. Amyloid beta is a protein fragment that is the principal component of Alzheimer’s plaques. Jae-Eun Kang, Ph.D., a post-doctoral fellow in Holtzman’s lab, noticed that brain amyloid 5) ___ levels in mice rose and fell in association with sleep and wakefulness, increasing in the night, when mice are mostly awake, and decreasing during the day, when they are mostly asleep. A separate study of amyloid beta levels in human cerebrospinal fluid led by Randall Bateman, M.D., assistant professor of neurology and a neurologist at Barnes-Jewish Hospital, also showed that amyloid beta levels were generally higher when subjects were awake and lower when they 6) ___. To confirm the link, Kang learned to use electroencephalography (EEG) on the mice at the Sleep and Circadian Neurobiology Laboratory at Stanford University with researchers Seiji Nishino, M.D., Ph.D., and Nobuhiro Fujiki, M.D., Ph.D. The EEG readings let researchers more definitively determine when mice were asleep or awake and validated the connection: Mice that stayed awake 7) ___ had higher amyloid beta levels. 

ANSWERS: 1) plaques; 2) sleep; 3) brain; 4) engineered; 5) beta; 6) slept; 7) longer

“Dung of The Devil” Plant Roots Still Relevant After 100 Years

Scientists in China have discovered that roots of a plant used a century ago during the great Spanish influenza pandemic contains substances with powerful effects in laboratory experiments in killing the H1N1 swine flu virus that now threatens the world. The plant was used in China against the influenza virus during the great 1918 Spanish flu epidemic, which is thought to have killed tens of millions worldwide. But until now no one has confirmed that Ferula assa-foetida has natural antiviral properties, according to a news release from the American Chemical Society. The plant has a pleasant onion-like taste when cooked, but when raw it has sap so foul-smelling that some call it the “Dung of the Devil” plant. Researchers found that Ferula Asafetida contained more than 230 natural healing compounds, and killed the H1N1 virus better than strong anti-viral drugs in lab tests, and prescription antiviral drugs available for the flu. Overall, the present study has determined that sesquiterpene coumarins from F. assa-foetida may serve as promising lead components for new drug development against influenza A (H1N1) viral infection. Ferula assa-foetida grows mainly in Iran, Afghanistan and mainland China.

On-Pump versus Off-Pump Coronary-Artery Bypass Surgery

Coronary-artery bypass grafting (CABG) has traditionally been performed with the use of cardiopulmonary bypass (on-pump CABG). As a result, a study published in the New England Journal of Medicine (2009;361:1827-1837) was performed to evaluate whether CABG surgery without cardiopulmonary bypass (off-pump CABG) might reduce the number of complications related to the heart-lung machine. The study randomly assigned 2,203 patients scheduled for urgent or elective CABG to either on-pump or off-pump procedures. The primary short-term end point was a composite of death or complications (reoperation, new mechanical support, cardiac arrest, coma, stroke, or renal failure) before discharge or within 30 days after surgery. The primary long-term end point was a composite of death from any cause, a repeat revascularization procedure, or a nonfatal myocardial infarction within 1 year after surgery. Secondary end points included the completeness of revascularization, graft patency at 1 year, neuropsychological outcomes, and the use of major resources. Results showed that there was no significant difference between off-pump and on-pump CABG in the rate of the 30-day composite outcome (7.0% and 5.6%, respectively; P=0.19). The rate of the 1-year composite outcome was higher for off-pump than for on-pump CABG (9.9% vs. 7.4%, P=0.04). The proportion of patients with fewer grafts completed than originally planned was higher with off-pump CABG than with on-pump CABG (17.8% vs. 11.1%, P<0.001). Follow-up angiograms in 1,371 patients who underwent 4,093 grafts revealed that the overall rate of graft patency was lower in the off-pump group than in the on-pump group (82.6% vs. 87.8%, P<0.01). There were no treatment-based differences in neuropsychological outcomes or short-term use of major resources. According to the authors, at 1 year of follow-up, patients in the off-pump group had worse composite outcomes and poorer graft patency than did patients in the on-pump group and there were no significant differences between the techniques in neuropsychological outcomes or use of major resources.

Sleep Quality and Immune Mediators in Asthmatic Children

Asthmatic children have been reported to complain about poor sleep quality and recent research has demonstrated a relationship between sleep and circulating cytokines. As a result, a study out of Taiwan, and published in Pediatrics and Neonatology (2009;50:222-229), was performed to assess the relationship between serum cytokine levels and sleep quality in asthmatic children. For the study, after an initial screening phase at allergy clinic visits, 90 asthmatic children aged 6-12 years were enrolled to complete the Chinese version of the (Childhood) Asthma Control Test (ACT). A questionnaire assessing sleep quality of asthmatic children was also administered to all subjects and parents. In addition, serum levels of interleukin (IL)-4, IL-6, IL-10, IL-12, total immunoglobulin (Ig) E, and prolactin were determined at enrollment. For the study, subjects with an ACT score = 20 were designated as the “well-controlled group” and those with a score of = 19 were designated as the “inadequately controlled group.” Results showed that in the well-controlled group, good sleepers had a significantly lower mean level of IL-10 and a higher mean ratio of IL-12/IL-10 compared with the poor sleepers. Furthermore, the serum prolactin level was significantly greater in the good sleeper subgroup. In both subgroups, the concentrations of IL-6, IL-12 and total IgE were not significant different. According to the authors, good sleep is associated with a lower IL-10 level, a higher prolactin concentration, and a higher IL-12/IL-10 ratio, and that prolactin may have a potential role in this immunity shift. The authors added that further insight into the functional role of cytokines on the sleep quality of asthma sufferers should result in the identification of novel therapeutic perspectives.

ONCOLOGY

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Prediagnostic Total and HDL Cholesterol and Risk of Cancer

Two studies on cholesterol levels and cancer risk have been recently reported and are summarized below. This area should be carefully studied to clearly clarify the risk. 

Circulating total cholesterol has been inversely associated with cancer risk. However, the role of reverse causation and the associations for high-density lipoprotein (HDL) cholesterol have not been fully characterized. The first study, published in Cancer Epidemiology Biomarkers and Prevention (2009;18:2814-2821), examined the relationship between serum total and HDL cholesterol and risk of overall and site-specific cancers among 29,093 men who participated in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) study. For the study, fasting serum total and HDL cholesterol were assayed at baseline, and 7,545 incident cancers were identified during up to 18 years of follow-up. Multivariable proportional hazards models were conducted to estimate relative risks (RR). Results showed that higher serum total cholesterol concentration (>276.7 versus <203.9 mg/dL) was associated with decreased risk of cancer overall (RR, 0.85; P trend <0.001). The inverse association was particularly evident for cancers of the lung and liver. These associations were no longer significant, however, when cases diagnosed during the first 9 years of follow-up were excluded. Greater HDL cholesterol ( >55.3 versus <36.2 mg/dL) was also associated with decreased risk of cancer (RR, 0.89; P trend = 0.01). The inverse association of HDL cholesterol was evident for cancers of lung, prostate, liver, and the hematopoietic system. In contrast with total cholesterol, the associations of HDL cholesterol with liver and lung cancers remained after excluding cases diagnosed within 12 years of study entry. According to the authors, the findings suggest that prior observations regarding serum total cholesterol and cancer are largely explained by reverse causation, and that although chance and reverse causation may explain some of the inverse HDL associations, some etiologic role for this lipid fraction cannot be ruled out.

Several prospective studies have suggested that use of cholesterol-lowering statin drugs is inversely associated with advanced stage and possibly high-grade prostate cancer, and one study reported that men with low cholesterol had a lower risk of high-grade prostate cancer. As a result, a study, published in Cancer Epidemiology Biomarkers and Prevention (2009;18:2807-2813), investigated the association between low serum cholesterol and prostate cancer risk in the Prostate Cancer Prevention Trial. The study evaluated 5,586 men ages   >   55 years who were randomized to the placebo arm of the Prostate Cancer Prevention Trial between 1993 and 1996. Serum cholesterol was measured enzymatically at entry, and by the end of follow-up, 1,251 prostate cancer cases were confirmed. Logistic regression was then used to calculate the multivariable odds ratio (OR) of Gleason 2 to 6 (n = 993), 7 (n = 199), and 8 to 10 (n = 59) prostate cancer, with low serum (normal, <200 mg/dL) to high-serum (borderline and elevated cholesterol, =200 mg/dL) cholesterol. Results showed that men with low cholesterol had a lower risk of Gleason 8 to 10 prostate cancer (OR, 0.41) than men with high cholesterol. No association was present for prostate cancer overall, Gleason 2 to 6 disease, or Gleason 7 disease. According to the authors, the study results support that men with low cholesterol have a reduced risk of high-grade prostate cancer and that these and other contemporary data suggest that cholesterol metabolism should be investigated further in the etiology of prostate cancer.

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.

Fast Track 

Speeding the development and availability of drugs that treat serious diseases are in everyone’s interest, especially when the drugs are the first available treatment or have advantages over existing treatments. The FDA has developed three distinct and successful approaches to making such drugs available as rapidly as possible: Priority Review, Accelerated Approval, and Fast Track. Because each of these approaches implies speed, there can be confusion about the specific meaning of each and the distinctions among them. The following summary describes Fast Track. The other areas will be subjects in the next editions of ON TARGET. 

Fast track is a process designed to facilitate the development, and expedite the review of drugs to treat serious diseases and fill an unmet medical need. The purpose is to get important new drugs to the patient earlier. Fast Track addresses a broad range of serious diseases. Determining whether a disease is serious is a matter of judgment, but generally is based on whether the drug will have an impact on such factors as survival, day-to-day functioning, or the likelihood that the disease, if left untreated, will progress from a less severe condition to a more serious one. AIDS, Alzheimer’s, heart failure and cancer are obvious examples of serious diseases. However, diseases such as epilepsy, depression and diabetes are also considered to be serious diseases. Filling an unmet medical need is defined as providing a therapy where none exists or providing a therapy which may be potentially superior to existing therapy. Any drug being developed to treat or prevent a disease with no current therapy obviously is directed at an unmet need. If there are existing therapies, a fast track drug must show some advantage over available treatment, such as:

  • Showing superior effectiveness
  • Avoiding serious side effects of an available treatment
  • Improving the diagnosis of a serious disease where early diagnosis results in an improved outcome
  • Decreasing a clinically significant toxicity of an accepted treatment
  • A drug that receives Fast Track designation is eligible for some or all of the following:
  • More frequent meetings with FDA to discuss the drug’s development plan and ensure collection of appropriate data needed to support drug approval
  • More frequent written correspondence from FDA about such things as the design of the proposed clinical trials
  • Eligibility for Accelerated Approval, i.e., approval on an effect on a surrogate, or substitute endpoint reasonably likely to predict clinical benefit
  • Rolling Review, which means that a drug company can submit completed sections of its New Drug Application (NDA) for review by FDA, rather than waiting until every section of the application is completed before the entire application can be reviewed. NDA review usually does not begin until the drug company has submitted the entire application to the FDA, and
  • Dispute resolution if the drug company is not satisfied with an FDA decision not to grant Fast Track status.

In addition, most drugs that are eligible for Fast Track designation are likely to be considered appropriate to receive a Priority Review. Fast Track designation must be requested by the drug company. The request can be initiated at any time during the drug development process. FDA will review the request and make a decision within sixty days based on whether the drug fills an unmet medical need in a serious disease. Once a drug receives Fast Track designation, early and frequent communication between the FDA and a drug company is encouraged throughout the entire drug development and review process. The frequency of communication assures that questions and issues are resolved quickly, often leading to earlier drug approval and access by patients.

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