On Target is Going on Vacation – “See you in September“

 

While Target Health continues full speed ahead getting products to the market, ON TARGET, one of the most popular non-commercial newsletters in the industry, is taking a break to recharge its batteries.

 

More Mountain Goats From Colorado

 

Two weeks ago we featured a Mountain Goat from Colorado. In response to that photo, our son Daniel, who lives in Colorado, sent us the photo below and said “the goats are great. I see them all the time. The kids are really cute.“

 

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©Target Health Inc. 2015

 

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

 

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The Health Crisis in Greece

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With some Greek pharmaceutical companies threatening to withhold products if they are not paid immediately, fears are spreading that there will soon be a shortage in hospitals of essential medicines and medical supplies. Greek physicians are saying that they are not able to care for their patients. The suicide rate continues to 1) ___.

 

Greece’s health crisis is worsening as a result of continued healthcare budget cuts, says a study published in The Lancet. The authors said that the harmful effects of austerity are linked to the increasing inability of patients to access the health system, large rises in the incidence of infectious 2) ___, and a deterioration in the overall mental health of Greek people. The authors from the University of Oxford, the University of Cambridge and the London School of Hygiene and Tropical Medicine find that Greece has had the largest cutbacks to the health sector seen across Europe, as the bailout package capped public expenditure at 6% of GDP. For example, from 2009 to 2011, the public hospital budget was reduced by over 25%. Greece’s public spending on health is now less than any of the other pre-2004 European 3) ___ members. Lead author of the study, Alexander Kentikelenis of Cambridge University, said: “The data reveals that the Greek welfare state has failed to protect people at the time they needed support the most. A rapidly growing number of Greeks are losing access to healthcare from 4) ___ cuts and unemployment.“

 

Senior author Dr David Stuckler from the University of Oxford said: “The Greek government -along with their European partners — appears to have been in denial about austerity’s severe impact on 5) ___. The cost of austerity is being borne mainly by ordinary Greek citizens, who have been affected by the largest cutbacks to the health sector seen across Europe in modern times. We hope this research will help the Greek government mount an urgently needed response to these escalating human crises.“ At a time of increasing health need and falling incomes, Greece’s bailout agreement stipulated shifting the cost of healthcare to patients. The Greek government introduced new charges for visits to outpatient clinics and higher costs for medicines. General health services were also eroded, says the paper. The authors’ analysis of the latest available data from the EU Statistics on Income and Living Conditions revealed a 47% rise in people who felt they did not receive medically necessary healthcare. This increase was linked to a rising inability to afford care and the costs of 6) ___ to access health services, according to the authors. Rapidly increasing unemployment since 2009 meant a growing number of people no longer had any form of health cover, with an estimated 800,000 without unemployment benefits or the ability to access health services.

 

The paper details signs of the nation’s deterioration in health including:

 

1. HIV incidence has risen in injecting drug-users more than 10-fold from 2009 to 2012

2. Tuberculosis incidence among injecting 7) ___ users more than doubled in 2013

3. State funding for mental health decreased by 55% between 2011 and 2012

4. Major depression increased 2.5-fold between 2008 and 2011

5. Suicides increased by 45% between 2007 and 2011

6. Infant mortality jumped by 43% between 2008 and 2010

7. The proportion of children at risk of poverty increased from 28 in 2007 to 30% in 2011

 

The authors noted that experiences of other countries that have overcome financial crises, such as Iceland and Finland, suggest that by ring-fencing health and social budgets, governments can avoid some of the harmful effects of crisis taking their toll on the health of their populations. The study concluded that the Greek health-care system was in grave need of reform before the crisis, but the scale and speed of imposed change limited its capacity to respond to its population’s increased health needs. In addition, the authors added that: “The foundations for a well-functioning health-care system need structures that are accountable and coordinated — not denialism. These findings suggest that the people of 8) ___ deserve better.“  Sources: The Lancet, 2014: 383; ScienceDaily.com; Wikipedia

 

ANSWERS: 1) increase; 2) disease; 3) Union; 4) budget; 5) health; 6) travel; 7) drug; 8) Greece

 

Editor’s note: We’re eating a yogurt from Greece, every day.  Do you think if everyone did this, it would help the Greek economy, just a little?

 

Greek Medicine Before Hippocrates, from Great Literature by Homer

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Idealized portrayal of Homer dating to the Hellenistic period (8th century BCE) according to Herodotus, now in the British Museum.

 

Greek influence right up through the Renaissance, and still alive and well in the 21st Century

 

Mycenaean (early Greek) civilization collapsed between 1200 and 1100 BCE. From this time until the beginning of classical Greek civilization around 800 BCE, Greece entered a dark age. Writing and other evidence becomes very scarce. The period has come to be called the “Greek Dark Ages“ because this lack of evidence has meant that scholars know little for sure about what went on in Greece during the period. It is uncertain why Mycenaean civilization collapsed around 1100 BCE. This has been traditionally blamed on invasions by sea faring raiders. With the collapse of Mycenaean society and the disappearance of writing, we have very little evidence for events and daily life in Dark Age Greece. What we do have, however, are Homer’s epic poems, the Odyssey and the Iliad, some of the oldest works of literature in the Western world.

 

Greek literature began to emerge in this period. At first, all stories were transmitted orally – bards had sung the stories of heroes and events like the Trojan War for generations. Now such stories became more standardized, and people may have already begun writing them down. Though the Iliad and the Odyssey are attributed to Homer, they took shape as oral tales that were passed down through the generations. Trade routes were interrupted by the fall of the Mycenaeans, but the inhabitants of Greece quickly began to trade with overseas neighbors once again. At first, trade was very limited, but over time trade routes grew larger and more numerous than they had been under the Mycenaeans. Trade with Anatolia, Egypt, andPhoenicia (the area around modern day Lebanon) was particularly important. A major innovation that probably came as a result of such trade was the adoption, late in the Greek Dark Ages, of the alphabet. With the flourishing of Greek art and literature, the Dark Ages of Greece came to an end and Greece entered the classical period. The beginning of the classical period, the Archaic period, saw a continuation of many of these trends and saw Greece come into its own as a great civilization and the birth place of democracy..

 

The culture of Greece has evolved over thousands of years, beginning in Mycenaean Greece, through the Greek Dark Ages (way before BCE) and continuing most notably into Classical Greece, the era referred to as the Golden Age of Greece. Greek thought influenced the Roman Empire and its successor the Byzantine Empire. In ancient times, Greece was the birthplace of Western culture and democracy. Modern democracies owe a debt to Greek beliefs in government by the people, trial by jury, and equality under the law. The ancient Greeks pioneered in many fields that rely on systematic thought, including biology, medicine, geometry, history, philosophy, and physics. They introduced such important literary forms as epic and lyric poetry, history, tragedy, comedy and an ideal of beauty, all of which strongly influenced the Western world.

 

The Iliad and the Odyssey were written by Homer in about 800 BCE. Considered great epic poems of the Greeks, both works, especially the Iliad, offer some insight into ancient Greek medical practices before the time of Hippocrates (470 – 410 BCE). The Iliad recounts the 9th year of the legendary battle between the Trojans and the Achaeans (or Greeks), known as the Trojan War, which if it truly happened, is variously dated by historians and archaeologists as having occurred around or between 1334 BCE – 1184 BCE. The Odyssey narrates the fantastic adventures of Odysseus, one of the heroes of the Trojan War, on his journey back to his country and ends happily with reunion with his family. The Iliad on the other hand is a tragedy. It deals with the Wrath of Achilles, its hero, who, having quarreled with Agamemnon, King of the Achaeans, withdraws from the fighting. But Achilles’ dearest friend is slain by Hector, the greatest warrior and hero of the Trojans. Achilles reconciles with Agamemnon, fights again, and he kills Hector. Although the Iliad does not end with the death of its hero, we are reminded throughout the narrative that Achilles in the end will himself be killed. The Iliad has numerous graphic descriptions of wounds and the treatment of injuries. The Iliad begins with a description of a pestilence sent by the god Apollo to ravage the camp of the Achaeans besieging Troy.

 

Down from the peaks of Olympus he strode, wroth at heart, bearing on his shoulders his bow and covered quiver. The arrows rattled on the shoulders of the angry god, as he moved, and his coming was like the night. Then he sate him down apart from the ships and let fly a shaft: terrible was the twang of the silver bow. The mules he assailed first and the swift dogs, but thereafter on the men themselves he let fly his stinging arrows, and smote; and ever did the pyres of the dead burn thick.

 

Homer, writes about the power of Greek gods. The Greeks believed that the gods had power over mortals and controlled man’s destiny. When angered, the gods punished man in various ways: disease, plague, death, natural catastrophes, misfortunes etc. Appeasement of the gods through prayers, offerings and sacrifice was therefore a central aspect of daily life. It’s important to note that Homer began his tale with a description of pestilence. The important physicians of the Greeks in the Iliad were Machaon and Polidarius, sons of Asclepius. Asclepius is mentioned only once in the Iliad and he was not a god then, but he seems to have been renowned for his healing abilities for Homer refers to him as the “peerless physician.“ History tells us that the healers and those in need of healing invoked Asclepius’ name in prayer and healing ceremonies in temples and at home. A healing clan known as the Asclepiads claimed to be the descendants of Asclepius and to have inherited a knowledge and mystical power of healing from him. Asclepius was later elevated to divine status, and temples were built to him throughout the Mediterranean world well into late antiquity. Sick people visited those temples to be healed in a ritual known as “temple sleep.“ They lay down to sleep in the abaton or “dream room“ and were visited in their dreams by Asclepius or by one of his priests, who gave advice. In the morning the patient often is said to have departed cured. The remains of those temples may still be seen at Epidaurus, Cos, Athens, and elsewhere. The Romans know him as Aesculapius and he has come down to us as the god of medicine, his life story shrouded in myth and legend. Legend says that Asclepius’ father was the god Apollo, who was often considered to be a god of healing.

 

In many Greek stories, Apollo is often depicted as the bringer and reliever of plagues as in the Iliad. Homer says that when the physician Machaon was wounded, the Achaeans quickly took him away from the battlefront to their ships for speedy treatment for he was “worth a regiment“ since he was a surgeon of supreme skill in his ability “to cut an arrow and heal the wounds with his ointments.“ The passage reflects how the Greeks valued a good physician as well as implies that medication was applied to heal wounds. Of course, the service of a good surgeon is indispensable in battle from ancient to modern times. The numerous descriptions of wounds and traumas suffered by the warriors, fatal and non-fatal, provide us with information regarding the state of knowledge of anatomy in pre-Hippocratic times.

 

“Meges, the mighty spearman caught up this man and struck him with his sharp lance on the nape of the neck. The point came through between the jaws and severed his tongue at the root.“ “The spear-point, landing in his forehead, pierced the bone; darkness came down on his eyes, and he crashed in the melee like a falling tower.“ “As Peiros sprang away, Aetolian Thoas hit him in the chest with a spear, below the nipple, and the bronze point sank into his lung.“ “The spear was fixed in his heart, which had not yet stopped beating and shook it to the very butt till at last the god of battle stilled it with his heavy hand.“ Homer, Iliad

 

Homer’s Iliad shows that knowledge of anatomy was rudimentary at that time. The vital organs had names and the warrior knew where to strike to cause death. Most likely, in Homer’s time, in common with other ancient peoples, anatomical knowledge was derived from the battlefield, the sacrificial altar, and the preparation of food. Such activities were the beginnings of anatomical knowledge. The treatment of wounds consisted essentially in removing foreign bodies, washing, and the application of herbals. No bandaging is mentioned. The foreign body usually was an arrow, which was difficult to extract because of the barbs and the wound had to be enlarged. The liquid used for washing was warm water and herbal preparations were applied directly to the wound.

 

“But save me. Take me to the ship, cut this arrow out of my leg, wash the blood from it with warm water and put the right things on it – the plants they say you have learned about from Achilles who learned them from Chiron, the best of the Centaurs.“ “Patroclus laid him down, cut the sharp point of the arrow out of his thigh with a knife, and washed away the dark blood from the wound with warm water. Then he teased out the root of a bitter herb in his hands and applied it to the place. It was a sedative, which banished all his pain. The wound began to dry and the blood ceased to flow.“

 

“And the monstrous Hades himself was wounded by an arrow. Sick at heart and in excruciating pain, Hades found his way to high Olympus and the Palace of Zeus. The arrow had driven into his shoulder muscles and was draining his strength. Paeeon, the Healer spread soothing ointments on the wound and cured him.“ Homer, Iliad

 

As the passages above show, the nature of the drugs is not described except for assertions that they were soothing and that they killed the pain. Drugs were applied not because of a belief that they had natural healing properties but because they had magical powers. In Greek mythology, Chiron, the centaur, invented medicine in order to heal himself when he was wounded by Hercules. Chiron is known as the Master of Medicine. Chiron taught Asclepius the art of healing, which became the source of all divine medical knowledge among the Greeks . Chiron was also the teacher of the hero, Achilles, who was thought to have had some special medical knowledge. The Greek word pharmakon, usually translated as “drug“ originally designated a substance with magical powers. These powers did not need to be therapeutic but were the result of inherent qualities that were considered to be magic. In the Iliad, there is no mention of drinking a substance to ease or kill pain, considering that the pain from horrific wounds suffered by the warriors must have been excruciating. This is quite surprising since opium was already available in Greece at the time of Homer and even long before the fall of Troy. However in the Odyssey, Homer mentions a potion dispensed by Helen to her guests at a banquet and the description would seem to be consistent with the known effects of opium.

 

“Then Helen, daughter of Zeus, had had an idea. Into the bowl in which their wine was mixed, she slipped a drug that had the power of robbing grief and anger of their sting and banishing all painful memories. No one that swallowed this, dissolved in wine, could shed a single tear that day, even for the death of his mother and father, or if they put his brother or his own son to the sword and he were there to see it done.“ Homer, Odyssey

 

Homer mentions too, that the drug that had the power of

 

“banishing painful memories“ was given to Helen by an Egyptian woman and goes on to say that “the fertile soil of Egypt is very rich in herbs, many of which are beneficial in solution, though many are poisonous. And in medical knowledge, Egyptians are supreme among men.“

 

The reference to Egypt indicates Egyptian influence on Greek medical practice. As early as 3400 BCE, opium poppy was cultivated in lower Mesopotamia where it was known as the “joy plant.“ Babylonian knowledge of the plant and its euphoric effects was passed on to Egypt and in 1300 BCE, the Egyptians began cultivating poppy. Trade in opium flourished with the Phoenicians and Minoans who exported the profitable item across the Mediterranean Sea into Greece, Carthage, and Europe. A statue of a Minoan goddess (dated 1300-1250 BCE) wearing split poppy capsules as hairpins has been found in Crete. Unlike the Iliad, which deals with battles and wounds, the Odyssey describes the voyages and adventures of Odysseus returning from the Trojan War. The Odyssey is more fanciful and contains more magic elements and fairy tales than the Iliad. For example, incantations to stop bleeding are not found in the Iliad whereas in the Odyssey, it is mentioned that while hunting, a boar wounded Odysseus in the leg and his companions stopped the hemorrhage with an incantation. There is also an interesting passage describing a voyage undertaken by Odysseus to procure arrow poison.

 

“For there, too, went Odysseus in his swift ship in search of a deadly drug, that he might have herewith to smear his bronze-tipped arrows.“ Homer, Odyssey

 

Toxon in Greek means “bow“ and the plural, toxin means “bow and arrow.“ Toxicon pharmakon is therefore not a toxic drug but a drug for smearing arrows. Through the centuries the word “toxin“ evolved to denote “poison“, dropping the bow and arrow along the way. The most important reference to medicine in the Odyssey pertains to a passage wherein Eumaeus, scolded for having brought in a beggar, answers:

 

“Who seeks out a stranger from abroad, unless he be one of those that are masters of some public craft, a prophet, or a healer of ills or of evils, or a builder, or a divine minstrel, who gives delight with his song? For these men are bidden all over the boundless earth.“ Homer, Odyssey

 

“Healer of evils“ (or Ieter kakon in Greek) as the physician was known indicates that he treated diseases without resorting to surgery. Sigerist interpreted the passage above as illuminating the status of the pre-Hippocratic physician:

 

“He was not a warrior or a priest but a professional worker with a social status of a craftsman, like the carpenter or the minstrel, the status that he still had in the classical period. The passage also reveals that physicians were few and practiced as itinerants, as was still the case in the days of Hippocrates“

 

In all ancient civilizations, the chief source of medical history is literature – medical literature. In all ancient civilizations, medical texts are found among the oldest literary documents preserved. Prescriptions and incantations were often long and complicated, and therefore not easy to remember, hence they were recorded in writing at an early date. Other sources may come from non-medical books and documents: works of fiction, literary works, folklore, law codes, political manifestos, commercial accounts, diaries, memoirs as well as prayer books. Information about past medical practices can be found in such unorthodox and unlikely sources because medicine encompasses every field of human endeavor. Such sources reflect events and views of the period and may contain references to the treatment of ailments. Oftentimes diaries and memoirs tell us better than medical books what disease meant to an individual and how it affected his life. It is generally agreed that the Iliad and the Odyssey were composed in the style of oral poetry. Since oral composition is traditional, much of the subject matter of the poems has been handed down over centuries. The poems do not faithfully reflect the cultural and social conditions of any particular time, but rather a mixture of such conditions, spread over hundreds of years. Nevertheless, the poet reflects existing conditions in his own society to a much greater degree. Homer’s characters are heroic but their passions and problems are human and universal. They, however, clearly understood their world and their own position in it: 1) the gods were powerful and man was at their mercy; 2) man must keep the gods happy through prayers, offerings and sacrifices; 3) displeasing the gods resulted in disease, pestilence, or misfortune; 4) health was restored by divine intervention through supplication.

 

Modern Western medicine traces its foundation (after Homer) to Classical Greece, from about 800 BCE to about 200 BCE. Like all ancient peoples, Homer explains natural phenomena and disease in terms of magic and religion. The transition from magic to science was a gradual process that took. Centuries. Dr. J. Roelandt, Professor of Cardiology, (Thoraxcentre Erasmus MC ROTTERDAM, The Netherlands), gave the following additional information: There is an important passage on fibrinous pericarditis:

 

Homer describes “the hairy hearts of hoary heroes“. In those days, ancient Greek warriors wanted to make sure that the enemy was dead. When the fight was over they burst the chest with an axe. The heart was probably often exposed and they must have observed the hairy appearance of the exposed heart, which is typical in pericarditis. Pericarditis must have been common probably due to the prevalence of tuberculosis at that time“.

 

Sources: The Saylor Foundation; Learning Ancient Greek Medicine from Homer, R. Hajar, Hamad Medical Group; Wikipedia; 

 

Information about Greece in 2015, from The New Yorker

 

Discussion of Greek Crisis, The New York Times, Nobel Prize winning economist, Joseph Stiglitz

 

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Raphael’s inspired “Homer on Mount Parnassus.“

 

Greek influence right up through the Renaissance, and still alive and well in the 21st Century

 

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Homer and His Guide, by William-Adolphe Bouguereau (1825-1905), portraying Homer on Mount Ida, beset by dogs and guided by the goat herder Glaucus (as told in Pseudo-Herodotus)

 

Editor’s note: I was lucky enough to be invited to Greece for an archeological cruise in the Aegean, financed by American businessman, Leon Pomerance, who sponsored digs in Crete and Santorini.  The cruise ship was donated for this scientific expedition, by Greek shipbuilder, Peter Nomikos.  Others I knew on this cruise, were Dragoslav Ninkovic and Bruce Heezen from Lamont Geological Observatory and Greek professor S. Marinatos from Athens, all mentioned in the paper below, which you might find interesting.  The paper presents the idea that the Greek Dark Ages may have been caused by the huge volcanic explosion of Santorini, followed by a gigantic, destructive tsunami, all of which were many times more devastating than Krakatoa.  These natural events would have been enough to wipe out the civilizations that existed at that time.

 

Further historical reading 

 

 

Interim Results from Phase 3 Study, Merck’s Investigational Ebola Vaccine Show Efficacy

 

To date, the investigational Ebola vaccine candidate rVSV-ZEBOV has been administered to more than 9,000 people in phase 1, 2 and 3 clinical trials.

 

This week, Merck announced that rVSV-ZEBOV was found to have 100% efficacy in an analysis of interim data from a Phase 3 ring vaccination trial in Guinea. Preliminary conclusions from this study, which is continuing, were published in The Lancet (31 July 2015). The authors report that vaccine efficacy was 100% following vaccination with a single dose of the rVSV-ZEBOV vaccine. It appeared that all vaccinated individuals were protected against Ebola virus infection within 6 to 10 days of vaccination.

 

The rVSV-ZEBOV vaccine was initially engineered with support from the Public Health Agency of Canada and was licensed to NewLink Genetics Corporation. To make the vaccine, the vesicular stomatitis virus was weakened by removing one of its genes, which was then replaced with a single Ebola virus gene that cannot cause disease by itself. In late 2014, when the current Ebola outbreak was at its most severe, Merck licensed rVSV-ZEBOV from NewLink Genetics, with the goal of accelerating the assessment of this candidate vaccine. Since that time, Merck has helped to enable a broad development program, including the interim phase 3 efficacy results just released. To date, more than 4,000 participants have received the vaccine in this innovative trial, called “Ebola ?a suffit“ or “Ebola, that’s enough.“ The trial was conducted by a team that included researchers from the World Health Organization (WHO), the Norwegian Institute of Public Health, the Health Ministry of Guinea and Medecins sans Frontieres, among others. The results from this continuing study, as well as other studies already underway and additional studies to be conducted, will be used to support worldwide regulatory submissions.

 

Methods: For this open-label, cluster-randomized ring vaccination trial, suspected cases of Ebola virus disease in Basse-Guinee (Guinea, West Africa) were independently ascertained by Ebola response teams as part of a national surveillance system. After laboratory confirmation of a new case, clusters of all contacts and contacts of contacts were defined and randomly allocated 1:1 to immediate vaccination or delayed (21 days later) vaccination with rVSV-ZEBOV (one dose of 2×107 plaque-forming units, administered intramuscularly in the deltoid muscle). Adults (age >18 years) who were not pregnant or breastfeeding were eligible for vaccination. Block randomization was used, with randomly varying blocks, stratified by location (urban vs rural) and size of rings (<20 vs >20 individuals). The study is open label and masking of participants and field teams to the time of vaccination is not possible, but Ebola response teams and laboratory workers were unaware of allocation to immediate or delayed vaccination. Taking into account the incubation period of the virus of about 10 days, the prespecified primary outcome was laboratory-confirmed Ebola virus disease with onset of symptoms at least 10 days after randomization. The primary analysis was per protocol and compared the incidence of Ebola virus disease in eligible and vaccinated individuals in immediate vaccination clusters with the incidence in eligible individuals in delayed vaccination clusters.

 

Results: Between April 1, 2015, and July 20, 2015, 90 clusters, with a total population of 7651 people were included in the planned interim analysis. 48 of these clusters (4123 people) were randomly assigned to immediate vaccination with rVSV-ZEBOV, and 42 clusters (3528 people) were randomly assigned to delayed vaccination with rVSV-ZEBOV. In the immediate vaccination group, there were no cases of Ebola virus disease with symptom onset at least 10 days after randomization, whereas in the delayed vaccination group there were 16 cases of Ebola virus disease from seven clusters, showing a vaccine efficacy of 100% (p=0.0036). No new cases of Ebola virus disease were diagnosed in vaccinees from the immediate or delayed groups from 6 days post-vaccination. At the cluster level, with the inclusion of all eligible adults, vaccine effectiveness was 75.1% (p=0.1791), and 76.3% (p=0.3351) with the inclusion of everyone (eligible or not eligible for vaccination). 43 serious adverse events were reported; one serious adverse event was judged to be causally related to vaccination (a febrile episode in a vaccinated participant, which resolved without sequelae). Assessment of serious adverse events is ongoing.

 

According to the authors, the results of this interim analysis indicate that rVSV-ZEBOV might be highly efficacious and safe in preventing Ebola virus disease, and is most likely effective at the population level when delivered during an Ebola virus disease outbreak via a ring vaccination strategy.

 

In addition to the phase 3 trial in Guinea described above, other studies evaluating the rVSV-ZEBOV vaccine include the STRIVE (Sierra Leone Trial to Introduce a Vaccine against Ebola) phase 3 study currently being conducted by the Sierra Leone College of Medicine and Allied Health Sciences (COMAHS), Sierra Leone Ministry of Health and Sanitation and the US Centers for Disease Control and Prevention (CDC); and the PREVAIL (Partnership for Research on Ebola Vaccines in Liberia) phase 2 study being conducted by a Liberia-NIH partnership in Liberia.

 

Paralyzed Legs Move with New Non-Invasive Spinal Cord Stimulation

 

According to a study published online in the Journal of Neurotrauma (15 June 2015), 5 men with complete motor paralysis were able to voluntarily generate step-like movements thanks to a new strategy that non-invasively delivers electrical stimulation to their spinal cords. The strategy, called transcutaneous stimulation, delivers electrical current to the spinal cord by way of electrodes strategically placed on the skin of the lower back. This expands to nine the number of completely paralyzed individuals who have achieved voluntary movement while receiving spinal stimulation, though this is the first time the stimulation was delivered non-invasively. Previously it was delivered via an electrical stimulation device surgically implanted on the spinal cord. In the study, the men’s movements occurred while their legs were suspended in braces that hung from the ceiling, allowing them to move freely without resistance from gravity. Movement in this environment is not comparable to walking; nevertheless, the results signal significant progress towards the eventual goal of developing a therapy for a wide range of individuals with spinal cord injury.

 

In a study published a little over a year ago, it was reported that four men with complete motor paralysis were able to generate some voluntary movements while receiving electrical stimulation to their spinal cords. The stimulation came from a device called an epidural stimulator that was surgically implanted on the surface of the men’s spinal cords. On the heels of that success, the authors began developing a strategy for delivering stimulation to the spinal cord non-invasively, believing it could greatly expand the number of paralyzed individuals who could potentially benefit from spinal stimulation.

 

During this most recent study, five men — each paralyzed for more than two years — underwent a series of 45 minute sessions, once a week, for approximately 18 weeks, to determine the effects of non-invasive electrical stimulation on their ability to move their legs. In addition to stimulation, the men received several minutes of conditioning each session, during which their legs were moved manually for them in a step-like pattern. The goal of the conditioning was to assess whether physical training combined with electrical stimulation could enhance efforts to move voluntarily. For the final four weeks of the study, the men were given the pharmacological drug buspirone, which mimics the action of serotonin and has been shown to induce locomotion in mice with spinal cord injuries. While receiving the stimulation, the men were instructed at different points to either try to move their legs or to remain passive.

 

Results: At the initiation of the study, the men’s legs only moved when the stimulation was strong enough to generate involuntary step-like movements. However, when the men attempted to move their legs further while receiving stimulation, their range of movement significantly increased. After just four weeks of receiving stimulation and physical training, the men were able to double their range of motion when voluntarily moving their legs while receiving stimulation. The authors suggest that this change was due to the ability of electrical stimulation to reawaken dormant connections that may exist between the brain and the spinal cord of patients with complete motor paralysis. Surprisingly, by the end of the study, and following the addition of buspirone, the men were able to move their legs with no stimulation at all and their range of movement was — on average — the same as when they were moving while receiving stimulation. According to the authors, it’s as if some networks were reawakened so that once the individuals learned how to use those networks, they become less dependent and even independent of the stimulation. During the study, the authors also made extensive recordings of electrical signals generated in the calf muscle and the muscle directly below the calf while the men attempted to flex their feet during stimulation. Over time, these signals increased with the same amount of stimulation, further supporting the hypothesis of re-established communication between the brain and spinal cord.

 

A new study has been already initiated a new study to see whether these same men can be trained with non-invasive spinal stimulation to fully bear their weight, a feat that the four men with surgically implanted stimulators have already achieved. In addition, there is interest to see whether, similar to epidural stimulation, non-invasive stimulation can help individuals regain some autonomic functions lost due to paralysis such as the ability to sweat, regulate blood pressure, and control bladder and bowel function.

 

The online version of this news release contains an image showing legs before and after treatment as well as a video.

 

 

The Clinical Trial Master File – MHRA Inspectorate Blog

 

Editor’s Note:  If an eTMF is used, a lot of the issues identified below can be identified prior to an inspector’s visit, thus reducing the time needed to be onsite. Target Health has been using Target Document as the eTMF for 10 years with a recent FDA inspection specifically addressed our eTMF and the use of electronic signatures.

 

The following is from the MHRA Inspectorate Blog.

 

The trial master file (TMF) is the collection of essential documents which allows the conduct of a clinical trial to be reconstructed and evaluated. It is basically the story of how the trial was conducted and managed. The blog report highlights some of the issues which have been experienced by sponsors and inspectors attempting to manage and review the large amounts of documentation that exist in support of a trial.

 

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Before and After©Target Health Inc. 2015

 

What needs to be filed in the TMF? A common misunderstanding is that only those documents listed in section 8 of International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) good clinical practice (GCP) are required to be filed. This is incorrect and the documents listed in section 8 only provide half of the story, as a number of key areas are not included such as documentation associated with data management and Qualified Person (QP) certification.

 

Another common area on documentation is correspondence associated with key decision making and trial conduct. We all use email as a key method of communication yet the correspondence section in the TMF is often very sparse or lacks the relevant emails. When as an inspector we say that we will raise a deficiency against a problem, it’s often the case that a number of emails can be provided to explain the issue but it’s unclear why they were not present in the TMF in the first place.

 

The next significant issue is that for commercial sponsors, the most frequent major finding is in relation to record keeping and essential documents and we have had to (on more than one occasion) add extra inspector days in order to complete the inspection due to problems with access to and provision of the TMF. While it may be feasible in UK inspections to conduct a return visit (with all of the logistical issues this may also raise for the sponsor), for an inspection requested by the Committee on Medicinal Products for Human use (CHMP) as part of a marketing authorisation application, this can be problematic. If the inspected sponsor site is outside of the European Union (EU), the ability to add additional days is very limited and therefore problems with the provision of the TMF could result in the rejection of an application due to the inability to fully evaluate the compliance of the trial with GCP requirements.

 

Neither the legislation, or the expectations of MHRA have changed in relation to the TMF, however the way in which the TMF is now presented for inspection by organisations has changed significantly. We believe this is due to 2 factors. Firstly, the increased globalisation of clinical trials, with huge TMFs containing essential documents that are spread across the globe and shared between different organisations such as the sponsor, contract research organisations, investigator sites, laboratories etc. Secondly (and probably in response to the first point), TMFs are now becoming electronic.

 

There are many advantages to the use of eTMFs: TMFs are not alone in becoming electronic (eTMF); we all work electronically, for example the clinical trial approvals from the MHRA clinical trial unit are now electronic, and the digital world is most definitely upon the clinical trial world with the advent of electronic case report forms (CRFs), electronic patient reported outcomes, electronic data capture etc. There are many advantages to the use of eTMFs such as ease of access, traceability and the ability of staff throughout the world to input into, access and manage the same repository of information. The other significant advantage is the ability to reduce the paper mountain associated with each trial. But with the advent of new technologies there also comes the need to ensure that the systems function as required and can deliver additional benefits when compared to the systems that they replace.

 

Currently we are seeing a transition between paper and electronic systems. This, and the ongoing development of suitable eTMF platforms, means that inspectors have been spending a lot of time on GCP inspections in discussion with the organisation to determine what their TMF consists of and exactly where it all is. For example there may be an electronic system that houses the majority of trial-related essential documents, which is usually presented to inspectors as the eTMF. However in addition to this, we usually discover that there are paper documents that are not provided as part of the TMF, and also that there are electronic systems that store essential documents that are also not considered by the organisation to be part of the TMF.

 

While we don’t expect that the TMF is a single system that holds every document and we are happy to review a number of systems on inspection, it is expected that the organisation identifies all of these systems and has a clear understanding of the content of the TMF and where all of the essential documents are located. A simple way to achieve this is to have an overarching mapping document that lists all the essential documents and where they are located. As part of this exercise, organisations should also determine how this can be accessed by the inspectors; for example is a specific type of read-only access required? It is typical that consideration has not been given to providing suitable access for the inspection team to the various components of the TMF and fulfilling our expectation that we can navigate the TMF ourselves. It is common that the organisation being inspected provides expert users to navigate the inspection team around the eTMF. This should not be necessary following some basic training and an awareness of the eTMF structure; if you relate this back to the paper TMF we would not require someone to help us turn the pages of a folder once the various files have been relocated to the inspection room. We often ask the question to quality assurance personnel as to how they would access the TMF during one of their audits, as surely the same type of access would be needed?

 

In general we have found that eTMFs have been designed as a repository for documents, but access to and retrieval of those documents is equally as important for managing clinical trials. We have conducted inspections where the eTMF ?expert’ in the organisation has been unable to easily retrieve documents due to the manner in which they have been named or filed. It is clear that the technology is available to facilitate an eTMF that can comply with the regulations both from an inspection point of view but also as a tool to allow for the retention of essential documents, but the various requirements necessary to facilitate this needs to be part of the design and user requirement specification stage of the build of the system. Issues we have seen on inspection generally relate to poor system design rather than changing expectations of the inspectors. If we return to the paper TMF vs eTMF example then the implementation of an eTMF should enhance the management, retention and review of essential documents rather than making it more cumbersome.

 

Talk to your inspector!: Prior to an inspection, the inspector will send out a clear request in relation to expectations of the TMF, and will be happy to discuss the requirements and how the TMF will be provided. It is your opportunity to clearly describe how you intend to supply the documentation required to support the inspection and you should state what system access will be provided if multiple platforms are used. It’s important to take advantage of this opportunity to go over these requirements, not only could it save you from a critical finding on inspection, but if the inspection is in relation to a marketing authorisation application, it could prevent the refusal of the application on the grounds that the integrity of the data and compliance with GCP cannot be verified.

 

Baked Stuffed Fresh Figs

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World’s Easiest & Quickest Recipe, that’s also dee -licious!  ©Joyce Hays, Target Health Inc.

 

Ingredients

 

1 pint of fresh figs (about 10 figs) buy 3 figs per person

4 ounces Greek feta cheese

4 ounces Bulgarian feta cheese

4 ounces goat cheese

4 ounces gruyere cheese

Canola oil for greasing a pan

 

 

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Assemble the ingredients. ©Joyce Hays, Target Health Inc.

 

Directions

 

Preheat oven to 350

 

With a damp towel, wipe the fresh figs. Pull any stems off. On a cutting board, and with a sharp knife, cut a cross, but only cut to just below the middle of each fig. Be sure the knife doesn’t cut all the way through the fig.

 

Have your variety of cheese ready; or if you have a favorite cheese, stick to that one cheese (cheese choice is up to you).

 

Pinch each fig so that it opens up like a flower. Stuff each fig with cheese. Not too much cheese or the fig won’t retain its shape in the oven. Let me share one of the results of experimenting with this recipe: goat cheese is by far the creamiest most delicious cheese to use in stuffing the figs. By now, I’ve tried a total of 5 different cheeses.  I recommend goat cheese.

 

With canola oil, brush the oil around the pan. The size of the pan is determined by the number of figs you decide on. Put the stuffed figs in the pan.

 

If you plan to serve the figs as an appetizer, heat them in the oven just before you serve them. If you want them to be the dessert, have them ready to pop in the oven and heat for 10 to 15 to 20 minutes, depending on your oven. After 10 minutes, check the figs. You want the cheese to be melted.

 

Feel free to experiment with the stuffing for the fresh figs. I have only tried a variety of cheeses. I have served the figs as an appetizer with red wine or chilled white wine or along with a salad that has either fresh fruit in it or beets. I’ve also served as a dessert, the cheese stuffed figs, with other fruit like slices of apple and pears, with a selection of cheeses and crackers.

 

I’m thinking about the fresh figs as a garnish with ice cream or even with a fig cake. I would make a simple honey mixture with chopped almonds and/or chopped cashews and stuff the figs with this. Tofutti (soy cream cheese) might hold up better than the honey, so I’m going to try that first tofutti mixed with chopped almonds and/or chopped cashews (and maybe add a drop of honey to this). Anyway, hope you try the fig recipe for this week’s newsletter and enjoy it!

 

This weekend we were at Lincoln Center (Avery Fisher Hall to be exact), enjoying the first Mostly Mozart Concert.  We heard 2 short Bach pieces (one was the encore) and Brahms; but the most thrilling for me was Mozart’s Piano Concerto Number 20, beautifully played by Jeremy Denk.  This is one of the most exquisite pieces of music ever written.

 

We also saw the Momix Dance Company down at the Joyce Theater (dancing only).  Usually every August we go two  or three times to the Joyce Theater to see the Polobolus Dance Company, but for some reason they,

only appeared at BAM (Brooklyn Academy of Music), so we missed them this year.

 

Finally, we tried out a new Manhattan restaurant, Polo Bar another creation by Ralph Lauren.  It’s a very pretty restaurant with good American food.  We had fun with the waiters; basically, had a good time.

 

Mozart Piano Concerto # 20

 

We’re going on vacation and will be back after Labor Day.  Hope your summer is relaxing, safe and fun. See you in September.

 

 

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Here they are stuffed and ready to go into the oven.  ©Joyce Hays, Target Health Inc.

Photo from left to right: gruyere cheese, Bulgarian feta, goat cheese, Greek feta.

 

 

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The stuffed figs were delicious with this Napa Valley, icy sauvignon blanc, Chateau Montelena.  ©Joyce Hays, Target Health Inc.

 

From Our Table to Yours!

 

Bon Appetit!