Clinical Trial Collaborations Meeting – Boston: March 21-22, 2016

 

Another great meeting sponsored by The Conference Forum.

 

The Conference Forum and CenterWatch are pleased to present together for the first time a 2016 strategic conference on identifying better solutions to drive more efficient R&D operations, especially as it applies to outsourcing, clinical research and clinical care. The conference presents insightful ideas and challenges for both R&D operations, CRO and site executives to discover new ways of collaborating. Clinical Trial Collaborations is designed for senior level clinical operation executives from large, medium, and small pharmas, CROs and Sites.

 

Our friend and colleague Dr. Jeff Kasher, Founder, Patients Can’t Wait, will chair a session entitled: “Whatever the Outsourcing Model, What’s the Best Way to Manage it?“

 

The panelists include:

 

Murray Abramson, MD, VP, Global Clinical Operations, Biogen

Deirdre BeVard, VP, Development Operations, Nektar Therapeutics

Mitchell Katz, PhD, Executive Director, Medical Research Operations, Purdue Pharma

Jules Mitchel, MBA, PhD, President, Target Health Inc.

 

This session addresses the points of view from Clinical operation heads on what they really want from their external teams and both CROs and sponsors discuss what can be different for 2016 and 2017. The reality with clinical outsourcing is that it’s extremely people dependent. Once relationships are sourced and pharma settles on governing and economics, the relationship moves down to different levels into the project teams. Roles and responsibilities in hand-offs become a challenge, often cause delays and is where some of the biggest pressure points come from.

 

ON TARGET is the newsletter of Target Health Inc., a NYC – based, full – service, contract research organization (eCRO), providing strategic planning, regulatory affairs, clinical research, data management, biostatistics, medical writing and software services to the pharmaceutical and device industries, including the paperless clinical trial.

 

For more information about Target Health contact Warren Pearlson (212 – 681 – 2100 ext. 104). For additional information about software tools for paperless clinical trials, please also feel free to contact Dr. Jules T. Mitchel or Ms. Joyce Hays. The Target Health software tools are designed to partner with both CROs and Sponsors. Please visit the Target Health Website.

 

Joyce Hays, Founder and Editor in Chief of On Target

Jules Mitchel, Editor

 

QUIZ

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You Need to Know More About Neonicotinoids

 

Public Health: We Are What We Eat. If We Ingest Toxins, Don’t We, Eventually, Get Sick? Are Dying Honey Bees, Butterflies, Birds, and more, the Canaries in the Coal Mine?

 

As of 2011 to Present, seven neonicotinoids from different international companies are on the market.

 

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Photo: Female worker bee, by Richard Bartz and Beemaster, Hubert Seibring; Own work, CC BY-SA 2.5, via Wikimedia Commons

 

Neonicotinoids (sometimes shortened to neonics (“NEE-oh-Nicks“)) are a class of neuro-active insecticides chemically similar to 1)______.

 

Neonicotinoids, like nicotine, bind to nicotinic acetylcholine receptors of a cell and trigger a response by that cell. In mammals, nicotinic acetylcholine receptors are located in cells of both the central nervous system and peripheral nervous systems. In insects these receptors are limited to the central nervous system. Nicotinic acetylcholine receptors are activated by the neurotransmitter acetylcholine. While low to moderate activation of these receptors causes nervous stimulation, high levels overstimulate and block the receptors, causing paralysis and death. Acetylcholinesterase breaks down acetylcholine to terminate signals from these receptors. However, acetylcholinesterase cannot break down neonicotinoids and their binding is irreversible.

 

 

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R-nicotine (top) and desnitro-imidacloprid are both protonated in the body

 

Most neonicotinoids are water-2) _____ and break down slowly in the environment, so they can be taken up by the plant and provide protection from insects as the plant grows. Independent studies show that the photo degradation half-life time of most neonicotinoids is around 34 days when exposed to sunlight. However, it might take up to 1,386 days (3.8 years) for these compounds to degrade in the absence of sunlight and micro-organism activity. There is concern that neonicotinoids applied agriculturally might accumulate in aquifers. Referred to as systemic insecticides, neonicotinoids spread through the plant, making it resistant to predators. Neonics don’t require repeated applications in a hazmat suit, rain can’t wash them away – but then again, neither can your kitchen faucet. Unless you’re eating strictly organic, you’re eating neonicotinoids all the time.

 

The neonicotinoid family includes acetamiprid, clothianidin, imidacloprid, nitenpyram, nithiazine, thiaclopridand thiamethoxam. Imidacloprid is the most widely used insecticide in the world. Compared to organophosphate and carbamate insecticides neonicotinoids cause less toxicity in birds and mammals than insects. Some breakdown products are 3) _____. In the late 1990s neonicotinoids came under increasing scrutiny over their environmental impacts. Neonicotinoid use was linked in a range of studies to adverse ecological effects, including honey-bee colony collapse disorder (CCD), loss of butterfly species (including the beloved Monarch), ladybugs, lightning bugs and loss of birds due to a reduction in insect populations. In 2013, the European Union and a few non EU countries restricted the use of certain neonicotinoids.

 

The precursor to nithiazine was first synthesized by a chemist at Purdue University in 1970. Shell researchers found in screening that this precursor showed insecticide potential and refined it to develop nithiazine. In 1984 nithiazine’s mode of action was found to be as a postsynaptic acetylcholine receptor agonist, the same as nicotine. Nithiazine does not act as an acetylcholinesterase inhibitor, in contrast to the organophosphate and carbamate insecticides. While nithiazine has the desired specificity (i.e. low mammalian toxicity), it is not photostable – that is, it breaks down in sunlight, and thus is not commercially viable.

 

In 1985, Bayer patented imidacloprid as the first commercial neonicotinoid, and during the late 1990s, it became widely used. Beginning in the early 2000s, two other neonicotinoids, clothianidin and thiamethoxam entered the market. As of 2013, virtually all corn planted in the United States was treated with one of these two insecticides and various fungicides. As of 2014, about a third of US soybean acreage was planted with neonicotinoid treated seeds, usually imidacloprid or thiamethoxam. Neonicotinoids have been registered in more than 120 countries and in 2008, they represented 24% of the global market for insecticides. Neonicotinoids made up 80% of all seed treatment sales in 2008.

 

Imidacloprid is effective against sucking insects, some chewing insects, soil insects and fleas on domestic animals. It is systemic with particular efficacy against sucking insects and has a long residual activity. Imidacloprid can be added to the water used to irrigate plants. Controlled release formulations of imidacloprid take 2-10 days to release 50% of imidacloprid in water. It is applied against soil pests, seed, timber and animal pests as well as foliar treatments. As of 2013 neonicotinoids have been used In the U.S. on about 95% of corn and canola crops, the majority of cotton, sorghum, and sugar beets and about half of all soybeans. They have been used on the vast majority of fruit and vegetables, including apples, cherries, peaches, oranges, berries, leafy greens, tomatoes, and potatoes, to cereal grains, rice, nuts, and wine grapes.

 

United States

 

The US EPA operates a 15-year registration review cycle for all pesticides. The EPA granted a conditional registration to clothianidin in 2003. v Thiamethoxam is approved for use as an antimicrobial pesticide wood preservative and as a pesticide it was first approved in 1999. Imidacloprid was registered in 1994. As all neonicotinoids were registered after 1984, they were not subject to reregistration. However, due to environmental concerns, especially concerning bees, the EPA opened dockets to evaluate them. The registration review docket for imidacloprid opened in December 2008, and the docket for nithiazine opened in March 2009. To best take advantage of new research as it becomes available, the EPA moved ahead the docket openings for the remaining neonicotinoids on the registration review schedule (acetamiprid, clothianidin, dinotefuran, thiacloprid, and thiamethoxam) to FY 2012. The EPA has said that it expects to complete the review for the neonicotinoids in 2018. In March 2012, the Center for Food Safety, Pesticide Action Network, Beyond Pesticides and a group of beekeepers filed an Emergency Petition with the EPA asking the agency to suspend the use of clothianidin. The agency denied the petition. In March 2013, the US EPA was sued by the same group, with the Sierra Club and the Center for Environmental Health joining, which accused the agency of performing inadequate toxicity evaluations and allowing insecticide registration based on inadequate studies. On July 12, 2013, Rep. John Conyers, on behalf of himself and Rep. Earl Blumenauer, introduced the “Save American Pollinators Act“ in the House of Representatives. The Act called for suspension of the use of four neonicotinoids, including the three recently suspended by the European Union, until their review is complete, and for a joint Interior Department and EPA study of bee populations and the possible reasons for their decline. The bill was assigned to a congressional committee on July 16, 2013 and did not leave committee.

 

Europe

 

In 2008, Germany revoked the registration of clothianidin for use on seed corn after an incident that resulted in the death of millions of nearby honey bees. An investigation revealed that it was caused by a combination of factors:

1. failure to use a polymer seed coating known as a “sticker“

2. weather conditions that resulted in late planting when nearby canola crops were in bloom;

3. a particular type of air-driven equipment used to sow the seeds which apparently blew clothianidin-laden dust off the seeds and into the air as the seeds were ejected from the machine into the ground;

4. dry and windy conditions at the time of planting that blew the dust into the nearby canola fields where honey bees were foraging;

In response to the study, the European Commission recommended a restriction of their use across the European Union. On 29 April 2013, 15 of the 27 EU member states voted to restrict the use of three neonicotinoids for two years starting 1 December 2013. Eight nations voted against the ban, while four abstained. The law restricts the use of imidacloprid, clothianidin and thiamethoxam for seed treatment, soil application (granules) and foliar treatment in crops attractive to bees.

 

Editor’s note: Not mentioned in any report are the numbers of jobs made available if organic pest control measures were substituted for the harmful chemical pesticide models.  Also, never studied are the effect on birds, bees, butterflies, humans, of the unavoidable combination of the daily ingestion of toxic drinking water, toxic inhaled air, toxic soil, toxins in non-organically grown food, toxic ocean food sources. Even if there are only trace chemicals in each source, the combination of toxic chemicals from all of  these substances, necessary for survival, on a daily basis, could be a tipping point for all living things.

 

Mammals and insects have different composition of the receptor subunits and the structures of the receptors. Because most neonicotinoids bind much more strongly to insect neuron receptors than to mammal neuron receptors, these insecticides are more toxic to insects than mammals. The low mammalian toxicity of imidacloprid has been explained by its inability to cross the blood-4) _____ barrier because of lack of a charged nitrogen atom at physiological pH. The uncharged molecule can penetrate the insect blood-brain barrier. Other neonicotinoids have a negatively charged nitro or cyano group, which interacts with a unique, positively charged amino acid residue present on insect, but not mammalian nAChRs. However, the breakdown product desnitro-imidacloprid, which is formed in a mammal’s body during metabolism as well as in environmental breakdown, has a charged nitrogen and shows high affinity to mammalian nAChRs. Desnitro-imidacloprid is quite toxic to mice.

 

Which species is the canary in the gold mine? What are we waiting for?

 

A dramatic rise in the number of annual beehive losses noticed around 2006 spurred interest in factors potentially affecting bee health. When first introduced, neonicotinoids were thought to have low toxicity to many insects, but recent research has suggested a potential toxicity to honey bees and other beneficial insects even with low levels of contact. Neonicotinoids may impact bees’ ability to forage, learn and remember navigation routes to and from food sources. Separate from lethal and sub-lethal effects solely due to neonicotinoid exposure, neonicotinoids are also being explored with a combination with other factors, such as mites and pathogens, as potential causes of colony collapse 5) _____. Neonicotinoids may be responsible for detrimental effects on bumble bee colony growth and queen production. For example, Bombus affinis, a bumblebee endemic to North America, has decreased in nearly 90% of its natural habitats, much of which has been attributed to the use of neonicotoid based pesticides. Previously undetected routes of exposure for bees include particulate matter or dust, pollen and nectar. Bees can fail to return to the hive without immediate lethality due to sub-nanogram toxicity, one primary symptom of colony collapse disorder. Separate research showed environmental persistence in agricultural irrigation channels and soil.

 

A 2012 study showed the presence of thiamethoxam and clothianidin in bees found dead in and around hives situated near agricultural fields. Other bees at the hives exhibited tremors, uncoordinated movement and convulsions, all signs of insecticide poisoning. The insecticides were also consistently found at low levels in soil up to two years after treated seed was planted and on nearby dandelion flowers and in corn pollen gathered by the bees. A 2013 review concluded that neonicotinoids, as they are typically used, harm bees and that safer alternatives are urgently needed. An October 2013 study by Italian researchers demonstrated that neonicotinoids disrupt bees’ immune systems, making them susceptible to viral infections to which the bees are normally resistant. In April 2015, the European Academies Science Advisory Council (EASAC) reported a study of the potential effects on organisms providing a range of ecosystem services like pollination and natural pest control which are critical to sustainable agriculture. The resulting report concludes “there is an increasing body of evidence that the widespread prophylactic use of neonicotinoids has severe negative effects on non-target organisms that provide ecosystem services including pollination and natural pest control.“ Two studies published in Nature provided further evidence of the deleterious effect of neonicontinoids on bees, although the further research is needed to corroborate the findings: Oilseed rape seed coated with a combination of clothianidin and a pyrethroid “reduced wild bee density, solitary bee nesting, and bumblebee colony growth and reproduction under field conditions. An October 2015 study demonstrated significant effects on the survival and reproductive capacities of honey bee queens exposed to neonicotinoids. Those exposed to neonicotinoids had 60% survival rates, as compared to 80% for control groups. Lower worker egg production and alterations to surviving queens’ reproductive anatomy “likely corresponded to reduced queen success (alive and producing worker offspring).“

 

Other Wildlife

In March 2013, the American Bird Conservancy published a commentary on 200 studies on neonicotinoids calling for a ban on neonicotinoid use as seed treatments because of their toxicity to birds, aquatic invertebrates, and other wildlife. A 2013 Dutch study found that water containing allowable concentrations of imidacloprid had 50% fewer invertebrate species compared with uncontaminated water. A later study found the analysis was confounded with other co-occurring insecticides and did not show imidacloprid directly affected invertebrate diversity. In the July 2014 issue of the journal Nature, a study based on an observed correlation between declines in some bird populations and the use of neonicotinoid pesticides in the Netherlands demonstrated that the level of neonicotinoids detected in environmental samples correlated strongly with the decline in populations of insect-eating birds.[

 

What is Organic and Why Does it Matter?

Organic is a term defined and controlled by the United States Department of Agriculture (USDA). The USDA Organic 6) _____ was first introduced in late 2002, allowing consumers to choose fruits, veggies, dairy, and meat produced without pesticides, genetic engineering, growth hormones, or irradiation. To qualify for an organic seal, farmers must adhere to the strict USDA rules for how animals are raised, how crops are planted and grown, and how waste is treated. The organic methods encourage sustainable farming, soil conservation, and also biodiversity. When raising farm animals, they are to be outdoors as much as possible with ample access to pasture. The Organic Seal assures that the product has been certified by a USDA accredited certification agency (such as Oregon Tilth). If a product is marked knowingly with an organic claim and is not produced and handled according to USDA standards and regulations, the company could be slapped with a hefty civic penalty up to $10,000.

 

 

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Whole Foods is only the most visible face of the newly confident organic industry. In February, Consumer Reports announced that sales of organic products had gone up 25% a year during the past decade, reaching $15 billion in 2004-out of a total U.S. food system worth a trillion dollars – and that nearly two-thirds of American consumers bought organic foods last year, paying, on average, a 50% premium over conventional foods. In March, Wal-Mart made the remarkable announcement that it would double its organic-grocery offerings immediately

 

Read more

 

Answers: 1) nicotine; 2) soluble; 3) toxic; 4) brain; 5) disorder; 6) seal

 

 

Agricultural Methods Affect Public Health, Bird, Bee & Insect Health: Honeybees

 

“Leave me the birds and the bees, please“ (Bob Dylan, Big Yellow Taxi)

 

Beekeeping (or apiculture, from Latin: apis “bee“) is the maintenance of honey bee colonies, commonly in hives, by humans. A beekeeper (or apiarist) keeps bees in order to collect their honey and other products that the hive produces (including beeswax, propolis, pollen, and royal jelly), to pollinate crops, or to produce bees for sale to other beekeepers. A location where bees are kept is called an apiary or “bee yard“.

 

 

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Honey seeker depicted on 8000-year-old cave painting near Valencia, Spain

 

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Beekeeping, tacuinum sanitatis casanatensis (14th century)

 

At some point humans began to attempt to domesticate wild bees in artificial hives made from hollow logs, wooden boxes, pottery vessels, and woven straw baskets or “skeps“. While beekeeping in pottery vessels began about 9,000 BCE and traces of beeswax are found in pot sherds throughout the Middle East beginning about 7000 BCE, depictions of humans collecting honey from wild bees date as far as 15,000 years ago. Domestication is shown in Egyptian art from around 4,500 years ago. Simple hives and smoke were used and honey was stored in jars, some of which were found in the tombs of pharaohs such as Tutankhamun. However, it wasn’t until the 18th century that European understanding of the colonies and biology of bees allowed the construction of the moveable comb hive so that honey could be harvested without destroying the entire colony.

 

 

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The Beekeepers, 1568, by Pieter Bruegel the Elder

 

On the walls of the sun temple of Nyuserre Ini from the Fifth Dynasty (before 2422 BCE), workers are depicted blowing smoke into hives as they are removing honeycombs. Inscriptions detailing the production of honey are found on the tomb of Pabasa from the Twenty-sixth Dynasty (c. 650 BCE), depicting pouring honey in jars and cylindrical hives. Sealed pots of honey were found in the grave goods of pharaohs such as Tutankhamun. There was documented attempt to introduce bees to dry areas of Mesopotamia in the 8th century BCE by Shamash-resh-u’ur, the governor of Mari and Suhu. His plans were detailed in a stele of 760 BCE

 

 

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Stele showing Shamash-resh-u-ur praying to the gods Adad and Ishtar with an inscription in Babylonian cuneiform

 

Translation: I am Shamash-resh-u-ur , the governor of Suhu and the land of Mari. Bees that collect honey, which none of my ancestors had ever seen or brought into the land of Suhu, I brought down from the mountain of the men of Habha, and made them settle in the orchards of the town ‘Gabbari-built-it’. They collect honey and wax, and I know how to melt the honey and wax – and the gardeners know too. Whoever comes in the future, may he ask the old men of the town, (who will say) thus: “They are the buildings of Shamash-resh-u-ur, the governor of Suhu, who introduced honey bees into the land of Suhu.“translated text from stele, (Dalley, 2002)

 

In prehistoric Greece (Crete and Mycenae), there existed a system of high-status apiculture, as can be concluded from the finds of hives, smoking pots, honey extractors and other beekeeping paraphernalia in Knossos. Beekeeping was considered a highly valued industry controlled by beekeeping overseers owners of gold rings depicting apiculture scenes rather than religious ones. Archaeological finds relating to beekeeping have been discovered at Rehov, a Bronze and Iron Age archaeological site in the Jordan Valley, Israel. Thirty intact hives, made of straw and unbaked clay, were discovered in the ruins of the city, dating from about 900 BCE. The hives were found in orderly rows, three high, in a manner that could have accommodated around 100 hives, held more than 1 million bees and had a potential annual yield of 500 kilograms of honey and 70 kilograms of beeswax. Thus, there is clear evidence that an advanced honey industry existed in ancient Israel 3,000 years ago.

 

In ancient Greece, aspects of the lives of bees and beekeeping are discussed at length by Aristotle. Beekeeping was also documented by the Roman writers Virgil, Gaius Julius Hyginus, Varro, and Columella. Beekeeping has also been practiced in ancient China since antiquity. In the book “Golden Rules of Business Success“ written by Fan Li (or Tao Zhu Gong) during the Spring and Autumn Period there are sections describing the art of beekeeping, stressing the importance of the quality of the wooden box used and how this can affect the quality of the honey. The ancient Maya domesticated a separate species of stingless bee. The use of stingless bees is referred to as meliponiculture, named after bees of the tribe Meliponini in Brazil. This variation of bee keeping still occurs around the world today.

 

 

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Rural beekeeping in the 16th century. Created in the 16th century by Jan-van-der-Straet Bauerlicher-Bienenstand

 

While limited occurrences resembling Colony Collapse Disorder (CCD) have been documented as early as 1869, this set of symptoms has, in the past several decades, been given many different names (disappearing disease, spring dwindle, May disease, autumn collapse, and fall dwindle disease). Most recently, a similar phenomenon in the winter of 2004/2005 occurred, and was attributed to varroa mites (the “vampire mite“ scare), though this was never ultimately confirmed. A well-documented outbreak of colony losses spread from the Isle of Wight to the rest of the UK in 1906. These losses later were attributed to a combination of factors, including adverse weather, intensive apiculture leading to inadequate forage, and a new infection, the chronic bee paralysis virus. However, at the time, the cause of this agricultural beekeeping problem was similarly mysterious and unknown. Reports show this behavior in hives occurring in the US in 1918 and 1919. When it was originally coined “mystery disease“ and eventually became more widely known as “disappearing disease“. From 1972 to 2006, dramatic reductions continued in the number of feral honey bees in the U.S. and a significant though somewhat gradual decline in the number of colonies maintained by beekeepers. This decline includes the cumulative losses from all factors, such as urbanization, pesticide use, tracheal and Varroa mites, and commercial beekeepers’ retiring and going out of business. However, in late 2006 and early 2007, the rate of attrition was alleged to have reached new proportions, and the term “colony collapse disorder“ began to be used to describe this sudden rash of disappearances (sometimes referred to as “spontaneous hive collapse“ or the “Mary Celeste syndrome“ in the United Kingdom). Losses had remained stable since the 1990’s at 17%-20% per year attributable to a variety of factors, such as mites, diseases, and management stress.

 

The first report of CCD was in mid-November 2006 by a Pennsylvania beekeeper overwintering in Florida. By February 2007, large commercial migratory beekeepers in several states had reported heavy losses associated with CCD. Their reports of losses varied widely, ranging from 30% to 90% of their bee colonies; in some cases, beekeepers reported losses of nearly all of their colonies with surviving colonies so weakened that they might no longer be able to pollinate or produce honey. Losses were reported in migratory operations wintering in California, Florida, Oklahoma, and Texas. In late February, some larger non-migratory beekeepers in the mid-Atlantic and Pacific Northwest regions also reported significant losses of more than 50%. Colony losses also were reported in five Canadian provinces, several European countries, and countries in South and Central America and Asia. In 2010, the USDA reported that data on overall honey bee losses for 2010 indicated an estimated 34% loss, which is statistically similar to losses reported in 2007, 2008, and 2009. Fewer colony losses occurred in the U.S. over the winter of 2013-2014 than in recent years. Total losses of managed honey bee colonies from all causes were 23.2% nationwide, a marked improvement over the 30.5% loss reported for the winter of 2012-2013 and the eight-year average loss of 29.6%. After bee populations dropped 23% in the winter of 2013, the Environmental Protection Agency and Department of Agriculture formed a task force to address the issue. In the six years leading up to 2013, more than 10 million beehives were lost, often to CCD, nearly twice the normal rate of loss.

 

Eylea Outperforms Avastin for Diabetic Macular Edema With Moderate Or Worse Vision Loss

 

NIH Website: Macular edema can arise during any stage of diabetic retinopathy and is the most common cause of diabetes-related vision loss. About 7.7 million Americans have diabetic retinopathy. Of these, about 750,000 have diabetic macular edema (DME). The National Eye Institute (NEI) provides information about diabetic eye disease and there is a NEI video about how diabetic retinopathy can be detected through a comprehensive dilated eye exam.

 

Eylea, Avastin, and Lucentis are all widely used to treat DME, a consequence of diabetes that can cause blurring of central vision due to the leakage of fluid from abnormal blood vessels in the retina. The macula is the area of the retina used when looking straight ahead. The drugs are injected into the eye and work by inhibiting vascular endothelial growth factor (VEGF), a substance that can promote abnormal blood vessel growth and leakage. Although the drugs have a similar mode of action, they differ significantly in cost. Based on Medicare allowable charges, the per-injection costs of each drug at the doses used in this study were about $1850 for Eylea, about $60 for Avastin, and about $1200 for Lucentis.

 

A two-year clinical trial published online in the journal Ophthalmology (27 February 2016), compared three drugs for diabetic macular edema (DME). Results showed that gains in vision were greater for participants receiving the drug Eylea (aflibercept; Regeneron) than for those receiving Avastin (bevacizumab; Genentech), but only among participants starting treatment with 20/50 or worse vision. Gains after two years were about the same for Eylea and Lucentis (ranibizumab), contrary to year-one results from the study, which showed Eylea with a clear advantage. The three drugs yielded similar gains in vision for patients with 20/32 or 20/40 vision at the start of treatment.

 

The study enrolled 660 people with DME at 89 clinical trial sites across the United States. When the study began, participants on average were 61 years old with 17 years of type 1 or type 2 diabetes. Only people with a visual acuity of 20/32 or worse were eligible to participate (to see clearly, a person with 20/32 vision would have to be 20 feet away from an object that a person with normal vision could see clearly at 32 feet). At enrollment, about half the participants had 20/32 to 20/40 vision. The other half had 20/50 or worse vision. In many states, a corrected visual acuity of 20/40 or better in at least one eye is required for a driver’s license that allows both day- and nighttime driving.

 

Each participant was assigned randomly to receive Eylea (2.0 milligrams/0.05 milliliter), Avastin (1.25 mg/0.05 mL), or Lucentis (0.3 mg/0.05 mL). Participants were evaluated monthly during the first year and every 4-16 weeks during the second year. Most participants received monthly injections during the first six months. Thereafter, participants received additional injections of assigned study drug until DME resolved or stabilized with no further vision improvement. Subsequently, injections were resumed if DME worsened. Additionally, laser treatment was given if DME persisted without continual improvement after six months of injections. Laser treatment alone was the standard treatment for DME until widespread adoption of anti-VEGF drugs a few years ago.

 

Results showed that among participants with 20/40 or better vision at the trial’s start, all three drugs improved vision similarly on an eye chart. On average, participants’ vision improved from 20/40 vision to 20/25. However, among participants with 20/50 or worse vision at the trial’s start, visual acuity on average improved substantially in all three groups. At two years, Eylea participants were able to read about 3.5 additional lines on an eye chart; Lucentis participants were able to read about three additional lines, and Avastin participants improved about 2.5 lines, compared with visual acuity before treatment. Eylea outperformed Avastin at the one- and two-year time points. While Eylea outperformed Lucentis at the one-year time point, by the two-year time point gains in visual acuity were not statistically different. At the end of the trial, average visual acuity was 20/32 to 20/40 among participants in all three groups.

 

According to the authors, the study results will help doctors and their patients with diabetic macular edema choose the most appropriate therapy. The authors added that the study suggests there is little advantage of choosing Eylea or Lucentis over Avastin when a patient’s loss of visual acuity from macular edema is mild, meaning a visual acuity of 20/40 or better. However, patients with 20/50 or worse vision loss may benefit from Eylea, which over the course of the two-year study outperformed Lucentis and Avastin. The number of injections participants needed was about the same for all three treatment groups. Eylea, Avastin, and Lucentis participants on average required nine injections in the first year of the study and five in the second year. The need for laser treatment varied among the three treatment groups. By two years, 41% of participants in the Eylea group received laser treatment to treat their macular edema, compared with 64% of participants in the Avastin group and 52% in the Lucentis group. The risk of heart attack, stroke, or death from a cardiovascular condition or an unknown cause by end of the trial was higher among participants in the Lucentis group. 12% of Lucentis participants had at least one event, compared with 5% of participants in the Eylea group and 8% of participants in the Avastin group. According to the authors, the difference in cardiovascular rates has not been seen across all other studies, and therefore may be due to chance. However, continued assessment of these serious cardiovascular events and their association with these drugs is important in future studies since cardiovascular events such as heart attack and stroke are common complications of diabetes. The occurrence of eye complications, such as eye infections and inflammation, was similar for all three drugs.

 

Population-Wide Impact of Long-term Use of Aspirin and Cancer Risk

 

The US Preventive Services Task Force recently recommended the use of aspirin to prevent colorectal cancer and cardiovascular disease among many US adults. However, the association of aspirin use with the risk for other cancer types and the potential population-wide effect of aspirin use on cancer, particularly within the context of screening, remain uncertain. Therefore, a study published online in JAMA Oncology 3 March 2016) was performed to examine the potential benefits of aspirin use for overall and subtype-specific cancer prevention at a range of doses and durations of use and to estimate the absolute benefit of aspirin in the context of screening.

 

Two large US prospective cohort studies, the Nurses’ Health Study (1980-2010) and Health Professionals Follow-up Study (1986-2012), followed up 135,965 health care professionals (88,084 women and 47,881 men, respectively) who reported on aspirin use biennially. The women were aged 30 to 55 years at enrollment in 1976; the men, aged 40 to 75 years in 1986. Final follow-up was completed on June 30, 2012, for the Nurses’ Health Study cohort and January 31, 2010, for the Health Professionals Follow-up Study cohort, and data were accessed from September 15, 2014, to December 17, 2015. The main outcome measures were relative risks (RRs) for incident cancers and population-attributable risk (PAR).

 

Results showed that among the 88,084 women and 47,881 men who underwent follow-up for as long as 32 years, 20,414 cancers among women and 7,571 cancers among men were documented. Compared with non-regular use, regular aspirin use was associated with a lower risk for overall cancer (RR, 0.97), which was primarily owing to a lower incidence of gastrointestinal tract cancers (RR, 0.85), especially colorectal cancers (RR, 0.81). The benefit of aspirin on gastrointestinal tract cancers appeared evident with the use of at least 0.5 to 1.5 standard aspirin tablets per week with the minimum duration of regular use associated with a lower risk was 6 years. Among individuals older than 50 years, regular aspirin use could prevent 33 colorectal cancers per 100,000 person-years (PAR, 17.0%) among those who had not undergone a lower endoscopy, and 18 colorectal cancers per 100,000 person-years (PAR, 8.5%) among those who had. Regular aspirin use was not associated with the risk for breast, advanced prostate, or lung cancer.

 

According to the authors, long-term aspirin use was associated with a modest but significantly reduced risk for overall cancer, especially gastrointestinal tract tumors, and that regular aspirin use may prevent a substantial proportion of colorectal cancers and complement the benefits of screening.

 

Congratulations to Robert Califf, MD, New FDA Commissioner

 

Robert M. Califf, MD, MACC, has been confirmed as the FDA’s Commissioner of Food and Drugs. As the top official of the FDA, Dr. Califf is committed to strengthening programs and policies that enable the agency to carry out its mission to protect and promote the public health. Previously, Dr. Califf served as the FDA’s Deputy Commissioner for Medical Products and Tobacco from February 2015 until his appointment as Commissioner in February 2016. In that capacity, he provided executive leadership to the Center for Drug Evaluation and Research (CDER), the Center for Biologics Evaluation and Research (CBER), the Center for Devices and Radiological Health CDRH), and the Center for Tobacco Products. He also oversaw the Office of Special Medical Programs and provided direction for cross-cutting clinical, scientific, and regulatory initiatives, including precision medicine, combination products, orphan drugs, pediatric therapeutics, and the advisory committee system.

 

Prior to joining the FDA, Dr. Califf was a professor of medicine and vice chancellor for clinical and translational research at Duke University. He also served as director of the Duke Translational Medicine Institute and founding director of the Duke Clinical Research Institute. A nationally and internationally recognized expert in cardiovascular medicine, health outcomes research, healthcare quality, and clinical research, Dr. Califf has led many landmark clinical trials and is one of the most frequently cited authors in biomedical science, with more than 1,200 publications in the peer-reviewed literature. Dr. Califf has served on the Institute of Medicine (IOM) committees that recommended Medicare coverage of clinical trials and the removal of ephedra from the market, as well as on the IOM Committee on Identifying and Preventing Medication Errors and the IOM Health Sciences Policy Board. He has served as a member of the FDA Cardiorenal Advisory Panel and FDA Science Board’s Subcommittee on Science and Technology. Dr. Califf has also served on the Board of Scientific Counselors for the National Institutes of Health and the National Library of Medicine, as well as on advisory committees for the National Cancer Institute, the National Heart, Lung, and Blood Institute, the National Institute of Environmental Health Sciences and the Council of the National Institute on Aging.

 

While at Duke, Dr. Califf led major initiatives aimed at improving methods and infrastructure for clinical research, including the Clinical Trials Transformation Initiative (CTTI), a public-private partnership co-founded by the FDA and Duke. He also served as the principal investigator for Duke’s Clinical and Translational Science Award and the NIH Health Care Systems Research Collaboratory coordinating center.

 

The Best Green Bean Salad You’ve Ever Tasted

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Green Bean Salad, Photo ©Joyce Hays, Target Health Inc.

 

Ingredients

1.5 pounds green beans

5 Tablespoons extra virgin olive oil (use your best), + 1 teaspoon

2 teaspoons chicken stock

4 Tablespoons balsamic vinegar (use your best)

1/2 cup capers

1 cup fresh basil, chopped

1 cup pine nuts, toasted

1 cup red seedless grapes, cut in half

Pinch salt

1 garlic clove, juiced (use 2 if you like garlic)

 

Directions

1. Toast the pine nuts in a fry pan, with 1 teaspoon olive oil, and 1-2 teaspoons chicken stock, stirring constantly for about 3 minutes. Then set aside on paper towel to drain any excess liquid from the nuts.

2. Steam the green beans, until slightly cooked, al dente, you do not want mushy. Rinse under cold water to stop them from cooking (and enhance the beautiful green color) and dry with paper towel. Depending on the length of the beans, cut them in half or in thirds.

3. In a small bowl, mix the Olive oil with the balsamic vinegar, garlic juice, pinch salt, pinch black pepper.

4. Into your salad bowl, add the green beans, basil and capers. Toss gently. Then, add the grapes. Slowly pour the dressing over the salad. Use a spatula to get every drop of the dressing poured over the salad. Toss. Finally, add the pine nuts, toss gently once more and serve.

 

You are in for a treat with this delicious salad as something wonderful happens when sweet grapes and sour capers combine, along with crunchy green beans, and toasted pine nuts. Basil adds a mysterious depth. Of course, gourmet olive oil and balsamic vinegar add their magic too. It’s rare to get such a delicious result from so few ingredients, and so little work. It’s taken me a long time, of trial and error, to get the exact delicious flavor mix, of this particular green bean salad.

 

Although, this salad would go with poultry, the best entre to serve would be fish or seafood. This salad could be served as a first course, then the fish with rice or polenta, and a cauliflower casserole or ratatouille or whatever veggie casserole you like. We had a selection of warm breads, chilled Sauvignon Blanc and a fruit and cheese platter.

 

Life is good!

 

 

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Spring is almost here, we needed some cheer, so our home is now filled with daffodils.  When it comes to chilled white wine, we keep coming back to Stag’s Leap Cellars Sauvignon Blanc and Santa Margherita Pinot Grigio. Both reliable, reasonably priced and delicious.

 

Cheers!

 

 

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From Our Table to Yours !

 

Bon Appetit!