FDA Pre-Approval Inspection (PAI) of Target Health for eSource Program – May 2015

 

Several weeks ago, FDA conducted a pre-approval inspection (PAI) at Target Health and at 3 leading oncology medical centers for a de novo 510(K). For this program, Target Health performed the following services: Regulatory Affairs, Clinical Research Management and Monitoring, Data Management, Biostatistics and Medical Writing. We are pleased to announce that for this 2nd inspection of Target Health, the previous inspection occurring in 2008, again NO FORM FDA 483 was issued. There were also NO FORM FDA 483 issues at 2 of the 3 medical centers. The finding at the 3rd center was related to just one procedure at the medical center and outside of the control of Target Health.

 

What was unique about this study, besides the product itself, was that Target e*CRF® fully integrated with Target e*CTR® (eClinical Trial Record) ® was used for data collection. Upon FDA review, there were no issues related to the eSource documents. For a drug program, an NDA is planned in Q3 2015. For this program there will also be global submissions.

 

To our friends and colleagues in clinical research and quality assurance, note that FDA focused on confirming that the:

 

1. Informed consent was provided and managed properly;

2. Protocol was followed;

3. Protocol was properly monitored;

4. The primary endpoint was properly recorded

5. All safety events were properly reported; and

6. Device performed as intended

 

View from the top of Stone Mountain (Stone Mountain State Park, NC)

 

Another masterpiece from our friend and colleague, James Farley, Director, Data Management and Programming, TransTech Pharma. Here is what he had to say about the experience. “This was my first time at the park. My wife and I, with our daughter, hiked the full loop! We headed down the direction of the falls first – at the advisement of one of the NC State Park rangers – and then up to the top of the mountain. The composition is on purpose, with the tree above the horizon at the third, with the leading-line of the rock out to the rocky surface of the facing peak, which is also set at the third.

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View from the top of Stone Mountain (Stone Mountain State Park, NC) – ©JFarly Photography 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

 

QUIZ

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Evolutionary Medicine

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The bacteria Mycobacterium tuberculosis can evolve to subvert the protection offered by immune defenses

 

Evolutionary medicine or Darwinian medicine is the application of modern evolutionary theory to understanding health and disease. The goal of evolutionary medicine is to understand why people get sick, not simply how they get 1) ___. Modern medical research and practice has focused on the molecular and physiological mechanisms underlying health and disease, while evolutionary medicine focuses on the question of why 2) ___ has shaped these mechanisms in ways that may leave us susceptible to disease. The evolutionary approach has driven important advances in our understanding of cancer, autoimmune disease, and anatomy. Medical 3) ___ have been slower to integrate evolutionary approaches because of limitations on what can be added to existing medical curricula. Adaptation works within constraints, makes compromises and tradeoffs, and occurs in the context of different forms of competition.

 

Adaptations can only occur if they are evolvable. Some adaptations which would prevent ill health are therefore not possible. For example:

 

1. DNA cannot be totally prevented from undergoing somatic replication corruption; this has meant that 4) ___, which is caused by somatic mutations, has not (so far) been completely eliminated by natural selection.

2. Humans cannot biosynthesize Vitamin C, and so they/we risk scurvy, a Vitamin C deficiency disease, if dietary intake of the vitamin is insufficient.

3. Retinal neurons and their axon output have evolved to be inside the layer of retinal pigment cells. This creates a constraint on the evolution of the visual system such that the optic 5) ____ is forced to exit the retina through a point called the optic disc. This in turn creates a blind spot. More importantly, it makes vision vulnerable to increased pressure within the eye (glaucoma) since this cups and damages the optic nerve at this point, resulting in impaired vision.

 

Other constraints occur as the byproduct of adaptive innovations. One constraint upon selection is that different adaptations can conflict, which requires a compromise between them to ensure an optimal cost-benefit tradeoff. Here are some trade-offs and conflicts:

 

1. Running efficiency in women, and birth 6) ____ size

2. Encephalization, and gut size

3. Skin pigmentation protection from UV, and the skin synthesis of Vitamin D

4. Speech and its use of a descended larynx, and increased risk of choking

 

Different forms of competition exist and these can shape the processes of genetic change. Here are a few examples:

 

1. mate choice and disease susceptibility

2. genomic conflict between mother and 7) ___ that results in pre-eclampsia

3. Major histocompatibility complex and its effect on mate choice

4. Maternal-paternal genetic competition that by altering genetic imprinting might underlie autism and schizophrenia

 

Humans evolved to live as simple hunter-8) ___ in small tribal bands, a very different way of life and environment compared to that faced by contemporary humans. This change makes present humans vulnerable to a number of health problems, termed “diseases of civilization“ and “diseases of affluence“. Humans were designed to live off of the land, and take advantage of the resources that were readily available to them. They were designed for the stone-age, and the environments of today bring about many disease causing ailments, that may or may not be deadly. “Modern environments may cause many diseases-for example, deficiency syndromes such as scurvy and rickets“ In contrast to the diet of early hunter-gatherers, the modern Western diet often contains high quantities of fat, salt, and simple carbohydrates, which include refined sugars and flours. These create health problems like: trans-fat health risks, dental caries, high glucose foods.

 

Some examples of aging-associated diseases are atherosclerosis and cardiovascular disease, cancer, arthritis, cataracts, osteoporosis, type 2 diabetes, hypertension and Alzheimer’s disease. The incidence of all of these diseases increases rapidly with aging (increases exponentially with age, in the case of cancer). Of the roughly 150,000 people who die each day across the globe, about two thirds – 100,000 per day – die of age-related causes. In industrialized nations, the proportion is much higher, reaching 90%. Many contemporary humans engage in little physical exercise compared to the physically active lifestyles of our ancestral hunter-gatherers. It has been proposed that since prolonged periods of inactivity would have only occurred in early humans following illness or injury that it provides a cue for the body to engage in life-preserving metabolic and stress related responses such as inflammation that are now the cause of many chronic 9) ___.

 

Contemporary humans – due to medical treatment, frequent washing of clothing and the body, and improved sanitation – are mostly free of parasites, particularly intestinal ones. This causes problems in the proper development of the immune system although hygiene can be very important when it comes to maintaining good health. The hygiene hypothesis says that many modern humans are not exposed to microorganisms that have evolved in establishing the immune 10) ___ as they should be. “Microorganisms and macroorganisms such as helminths from mud, animals, and feces play a critical role in driving immuno-regulation“ (Rook, 2012). They play a crucial role in building and training immune functions to fight off and repel some diseases, and protect against excessive inflammation which has been implicated in several diseases (such as recent evidence for Alzheimer’s Disease).

 

ANSWERS: 1) sick; 2) evolution; 3) schools; 4) cancer; 5) nerve; 6) canal; 7) fetus; 8) gatherers; 9) diseases; 10) system

 

Evolutionary Medicine

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Charles Darwin (1809-1882). In 1881 Darwin was an eminent figure, still working on his contributions to evolutionary thought that had an enormous effect on many fields of science. Portrait by John Collier. Hangs today in The National Portrait Gallery, London.

 

Charles Robert Darwin was an English naturalist and geologist, best known for his contributions to evolutionary theory. He established that all species of life have descended over time from common ancestors, and in a joint publication with Alfred Russel Wallace introduced his scientific theory that this branching pattern of evolution resulted from a process that he called natural selection, in which the struggle for existence has a similar effect to the artificial selection involved in selective breeding. Darwin published his theory of evolution with compelling evidence in his 1859 book On the Origin of Species, overcoming scientific rejection of earlier concepts of transmutation of species. By the 1870s the scientific community and much of the general public had accepted evolution as a fact. However, many favored competing explanations and it was not until the emergence of the modern evolutionary synthesis from the 1930s to the 1950s that a broad consensus developed in which natural selection was the basic mechanism of evolution. Darwin’s scientific discovery is now the unifying theory of the life sciences, explaining the diversity of life.

 

Charles Darwin did not discuss the implications of his work for medicine, though biologists quickly appreciated the germ theory of disease and its implications for understanding the evolution of pathogens, as well as an organism’s need to defend against them. Medicine, in turn, ignored evolution, and instead focused (as done in the hard sciences) upon proximate mechanical causes. Medicine modeled itself after a mechanical physics, deriving from Galileo, Newton, and Descartes. As a result, until recently, medicine was mechanistic, materialistic, reductionistic, linear-causal, and deterministic (capable of precise predictions) in its concepts. It sought explanations for diseases, or their symptoms, signs, and cause in a single, materialistic – i.e., anatomical or structural (e.g., in genes and their products) – changes within the body, wrought directly (linearly), for example, by infectious, toxic, or traumatic agents.

 

George C. Williams was the first to apply evolutionary theory to health in the context of senescence. Also in the 1950s, John Bowlby approached the problem of disturbed child development from an evolutionary perspective upon attachment. An important theoretical development was Nikolaas Tinbergen’s distinction made originally in ethology between evolutionary and proximate mechanisms. Randolph Nesse summarized its relevance to medicine by stating that all biological traits need two kinds of explanation, both proximate and evolutionary. The proximate explanation for a disease describes what is wrong in the bodily mechanism of individuals affected by it. An evolutionary explanation is completely different. Instead of explaining why people are different, it explains why we are all the same in ways that leave us vulnerable to disease. Why do we all have wisdom teeth, an appendix, and cells that can divide out of control? The paper of Paul Ewald in 1980, “Evolutionary Biology and the Treatment of Signs and Symptoms of Infectious Disease“, and that of Williams and Nesse in 1991, “The Dawn of Darwinian Medicine“ were key developments. The latter paper “drew a favorable reception“, and led to a book, Why We Get Sick (published as Evolution and healing in the UK).

 

Evolutionary medicine as a field began in the early 1990s, but has grown dramatically in recent years. These developments include the creation of the online publication, The Evolution & Medicine Review (which has served as a clearinghouse for important information in the field), two peer-reviewed journals (Evolution, Medicine and Public Health and Journal of Evolutionary Medicine), the founding of several evolution and cancer centers (The Center for Evolution and Cancer at UCSF and The Darwinian Evolution of Cancer Consortium in Montpellier) and The Center for Infectious Disease Dynamics at Penn State. There is now a national working group on evolutionary medicine education at the NSF sponsored National Evolutionary Synthesis Center, Infusing Medical Education with Evolutionary Thinking. Evolutionary Medicine programs have been established at a growing number of Universities, including UCLA, Arizona State University and Durham University in the UK.

 

NIH Study Solves Ovarian Cell Mystery, Shedding New Light on Reproductive Disorders

 

According to an article published online in the journal Nature Communications (28 April 2015), scientists at the National Institutes of Health have solved a long-standing mystery about the origin of one of the cell types that make up the ovary. The team also discovered how ovarian cells share information during development of an ovarian follicle, which holds the maturing egg. The authors believe this new information on basic ovarian biology will help them better understand the cause of ovarian disorders, such as premature ovarian failure and polycystic ovarian syndrome, conditions that both result in hormone imbalances and infertility in women. According to the authors, the ovarian follicle is the basic functional unit of the ovary, which contains the egg surrounded by two distinct cell types, known as granulosa cells and theca cells. Until now, the cellular origins of the egg and granulosa cells were known, but it was not known where theca cells came from or what directed their development. Without theca cells, women are unable to produce the hormones that sustain follicle growth. One of the major hormones theca cells produce is androgen, which is widely thought of as a male hormone. But, in a superb example of teamwork, the granulosa cells convert the androgen to estrogen.

 

The answer to this question remained unanswered for decades, but using a technique called lineage tracing, it was determined that theca cells in mice come from both inside and outside the ovary, from embryonic tissue called mesenchyme. According to the authors, “We don’t know why theca cells have two sources, but it tells us something important — a single cell type may actually be made up of different groups of cells.” As a result of this work, the authors uncovered the molecular signaling system that enables theca cells to make androgen. This communication pathway is derived from granulosa cells and another structure in the ovary called the oocyte, or immature egg cell. The crosstalk between the egg, granulosa cells, and theca cells was an unexpected finding, but one that may provide insight into how ovarian disorders arise. Now that it is known what makes these cells grow, the next steps are to search for possible genetic mutations or environmental factors that affect the process leading to ovarian cell disorders. For future work, the team wants to explore the two types of cells that make up theca cells. Since the research has been carried out in mice, it will need to be determined if the same holds true for humans. Either way, the research may potentially uncover several roles theca cells play in female fertility.

 

Near-Atomic Resolution of Protein Structure by Electron Microscopy Holds Promise for Drug Discovery

 

Drug development efforts often involve mapping contacts between small molecules and their binding sites on proteins. These mappings require the highest possible resolutions so that the shape of the protein chain can be traced and the hydrogen bonds between the protein and the small molecules it interacts with can be discerned. According to a study published online in Science Express 7 May 2015) a new study shows that it is possible to use an imaging technique called cryo-electron microscopy (cryo-EM) to view, in near-atomic detail, the architecture of a metabolic enzyme bound to a drug that blocks its activity. This advance provides a new path for solving molecular structures that may revolutionize drug development.

 

The protein imaged in this study was a small bacterial enzyme called beta-galactosidase; the drug to which it was bound is an inhibitor called phenylethyl-beta-D-thiogalactopyranoside (PETG), which fits into a pocket in the enzyme. Enzymes are typically proteins that act to catalyze biochemical reactions in the cell. Understanding what an enzyme looks like, both with and without a drug bound to it, allows researchers to design new drugs that can either block that enzyme’s function (if the function is responsible for a disease), or enhance its activity (if lack of activity is causing a problem).

 

In this study, the researchers were able to visualize beta-galactosidase at a resolution of 2.2 angstroms (or A — about a billionth of a meter in size), which is comparable to the level of detail that has thus far been obtained only by using X-ray crystallography. At these high resolutions, there is enough information in the structure to reliably assist drug design and development efforts. To determine structures by cryo-EM, protein suspensions are flash-frozen at liquid nitrogen temperatures (-1960C to -2100C , or -3200F to -3460F) so the water around the protein molecules stays liquid-like. The suspensions are then imaged with electrons to obtain molecular images that are averaged together to discern a three-dimensional (3D) protein structure. In the study, using about 40,000 molecular images, the authors were able to compute a 2.2 A resolution map of the structure of beta-galactosidase bound to PETG. This map not only allowed the authors to determine the positioning of PETG in the binding pocket but also enabled them to pick out individual ions and water molecules within the structure and to visualize in great detail the arrangement of the amino acids that make up the protein.

 

The authors have recently used cryo-EM to understand the functioning of a variety of medically important molecular machines, such as the envelope glycoproteins on HIV and glutamate receptors found in brain cells. Their new finding, however, represents the highest resolution that they or others have achieved to date for a structure determined by cryo-EM.

 

Spinal Cord Stimulation System Approved That Treats Pain Without Tingling Sensation

 

Back pain is a common disability for many Americans. Acute pain begins suddenly and is usually sharp in quality. Acute pain might be mild and last just a moment, or it might be severe and may last three to six months. In most cases, acute pain disappears when the underlying cause of pain has been treated or has healed. Unrelieved acute pain, however, might lead to chronic pain. Chronic pain is pain that lasts more than 12 weeks and may persist for years. Chronic pain might have originated with an initial trauma/injury or infection, or there might be an ongoing cause of pain. However, some people suffer chronic pain in the absence of any past injury or evidence of body damage.

 

The FDA has approved the Senza spinal cord stimulation (SCS) system (Senza System) as an aid in the management of chronic intractable pain of the trunk and/or limbs, including pain associated with failed back surgery syndrome, low back pain and leg pain. The Senza System can reduce pain without producing a tingling sensation called paresthesia by providing high frequency stimulation (at 10 KHz) and low stimulation amplitudes.

 

Before receiving treatment with the Senza System, patients participate in a one- to two-week simulation using an implanted trial lead and a model of the stimulus generator that is worn outside the body. Once it is determined that the stimulation works well based on the patient’s reporting of symptoms, the system is implanted via a minimally invasive surgical procedure. The system delivers electrical stimulation to the thoracolumbar area of the spinal cord (in the region of the mid to lower back) via leads implanted through a small incision in the patient’s back. The lead is connected to a rechargeable, implantable pulse generator that is implanted in the patient’s upper buttocks region or abdomen. A clinician initially programs the device, and patients can use a remote to control the pulse generator within the output ranges programmed by the clinician.

 

FDA’s review of safety and effectiveness included data from a clinical study. During the study, 198 subjects with chronic intractable pain of the trunk and/or limbs were randomized to either the Senza System test group or a control group. The control group was made up of 97 subjects treated with another FDA-approved device that delivers stimulation in the two to 1,200 Hz frequency range that produced paresthesia. Results showed that 75% of subjects treated with the Senza System achieved a 50% reduction in pain from baseline at three months, which was the primary target of the study, and an approximately 55% reduction at 12 months. There were no stimulation-related neurological deficits, such as weakness in the limbs or tremors, observed for either treatment group. The most common adverse events associated with the Senza System included pain at the implant site and dislocation of the device lead under the skin. The FDA also approved the Senza System for stimulation parameters below 10 KHz. For stimulation parameters, similar to those used in the control group and other traditional SCS systems, paresthesia is required. The Senza System is manufactured by Nevro Corp., based in Menlo, California.

 

Baked Eggplant Appetizer with Pesto & Mozzarella

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Ingredients

 

1 eggplant

Whites of 3 eggs

Extra virgin olive oil

Pinch salt

Pinch black pepper

3 Pinches chili flakes

1 teaspoon turmeric bought already mixed with black pepper

1 cup (more if needed) Panko (fine not large crumbs)

Pesto sauce (make it ahead of time)

Freshly made mozzarella

1 red pepper (for garnish)

1/2 cup Parmesan cheese, freshly grated

 

 

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Fresh, healthy, tasty ingredients ©Joyce Hays, Target Health Inc.

 

Directions

 

1. Make your pesto sauce ahead of time (see recipe below)

2. Preheat oven to 375

3. With a brush, oil a baking sheet

4. Cut the red pepper in half and clean out the seeds and white skin. Drizzle a little olive oil over the pepper, put on a large piece of foil and bake in the oven until it’s soft. When cool enough, slice red ribbons of pepper and set aside

5. In a small bowl whisk together, the 3 egg whites, teaspoon olive oil, pinch of salt, black pepper.

6. In another bowl put in the Panko, stir in the chili flakes, the parmesan cheese, the turmeric.

 

 

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Pesto sauce is easy with a food processer ©Joyce Hays, Target Health Inc.

 

7. Now, slice the eggplant into slices 1/2 inch thick and dip them first into the egg white mixture, then into the Panko/parmesan crumbs

 

 

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Bake, turn over, bake again. These are going back the second time. ©Joyce Hays, Target Health Inc.

 

8. Next, put the eggplant circles on the oiled baking sheet and bake until golden brown. When done, turn them over and bake until golden brown on the other side. When done, set aside until10 minutes before you’re ready to serve them.

 

 

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Be sure the mozzarella is fresh ©Joyce Hays, Target Health Inc.

 

9. While the eggplant is baking, cut the fresh mozzarella into slices ? to ? inches thick, then set aside.

 

 

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Just before serving, give yourself time to heat the appetizer (or side dish, or veggie with fish or eggplant with pasta): On the baking sheet, already used, put a slice of the mozzarella you’ve already cut, then a circle of the baked eggplant, then a generous 1/2 to 3/4 teaspoon of the pesto sauce, on top of the eggplant. Put these appetizer circles into the oven for 5 minutes, until they warm up and the mozzarella gets gooey.

 

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Arranged on a serving plate with the gooey mozzarella ©Joyce Hays, Target Health Inc.

 

Take out of oven, and arrange on a serving platter, or individual small appetizer plates, drizzling extra pesto sauce around the eggplant. As the last touch, add a tiny ribbon of roasted red pepper to the top of the eggplant circles, and serve immediately with a favorite cabernet sauvignon or pinot noir like (Napa Valley) Paul Hobbs or a well-chilled sauvignon blanc, like (New Zealand) Te Koko

 

 

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Back to one of our favorite Sauvignon Blanc from New Zealand, Te Koko ©Joyce Hays, Target Health Inc.

 

Jules is traveling on business, outside the U.S. leaving on a night flight, so we had a light repast before he left for JFK, including these eggplant appetizers with Te Koko sauvignon blanc. The eggplant circles are a delicious combo of many ingredients and are adaptable. For example, they could be a main dish (with rice or pasta or just some good bread) or side dish with any fish, or one of several veggie items offered at a meatless meal. Jules and I are trending toward more and more meat-free meals. We’re not vegan or paleo, just feeling better with less meat.

 

On the night that Jules left, this eggplant recipe was a perfect appetizer with the chilled white wine. A cautionary note: I’m still working on the mozzarella. If you plan to make this, I would suggest putting the slice of mozzarella on top of the already baked eggplant circle, then the pesto sauce, and finally, the ribbon of roasted red pepper. Put this into the 350 to 375 oven for five minutes to let the cheese melt a little, so you can serve it warm and gooey. Perfect with chilled wine and probably good with red also.

 

No theater this week. There is a story to tell, nevertheless. I had to have a root canal this week and always approach things like this (pain) with apprehension and dread. My last root canal ended with up at Mount Sinai Beth Israel Hospital, needing their best oral and maxillofacial surgeon to treat a terrible swollen infection, that required high doses of levaquin, a strong antibiotic for superbugs. Nearly hospitalized with 24 hour antibiotic IV. You can imagine how nail-biting this week’s root canal appointment was. However, I can report in glowing terms, that I have discovered the best dentist in all of NYC. What difference intelligence, personality and the latest equipment make! Plus, no pain! Like a miracle (worth sharing! In case you are ever in need of the best endodontist imaginable, his name is Joshua H. Brickman DMD, at 1414 Sixth Avenue (corner of West 58th Street, 19th floor).

 

So-o, this was a satisfying, excellent week!

 

From Our Table to Yours!

 

Bon Appetit!