Innovation at Target Health
Target Health is a full service eCRO. What differentiates us from others in the CRO industry is our commitment and proven ability to optimize and implement methods, including software products, to allow for the paperless clinical trial. Think about it, all email communications involve direct data entry as does the information that populates the electronic medical record.
Target e*CTR® (eClinical Trial Record; eSource), fully integrated with Target e*CRF® (and with potential to integrate with any EDC system) allows for direct data entry (DDE) at the time of the office visit. Applied Clinical Trials just informed us that they are reprinting a paper published online in January 2014, entitledTime to Change the Clinical Trial Paradigm, Applied Clinical Trials, January 2014 will be published in a paper edition for the annual DIA meeting in San Diego. Visit our website for more information about our software products.
Turtles Sunning at the Edge of the Central Park Reservoir ©Target Health Inc.
ON TARGET is the newsletter of Target Health Inc., a NYC-based contract research organization (eCRO), providing strategic planning, regulatory affairs, clinical research, data management, biostatistics, medical writing and software services, including the paperless clinical trial, to the pharmaceutical and device industries.
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 Chief Editor of On Target
Jules Mitchel, Editor
Ernst 23Haeckel’s Paleontological Tree of Vertebrates (c. 1879).The evolutionary history of species has been described as a tree, with many branches arising from a single trunk. While Haeckel’s tree is somewhat outdated, it illustrates clearly the principles that more complex modern reconstructions can obscure.
Evolution by natural 1) ___, the central concept of the life’s work of Charles Darwin, is a theory. It’s a theory about the origin of adaptation, complexity, and diversity among Earth’s living creatures. Evolution is the unifying force in modern biology; it ties together fields as disparate as genetics, microbiology and paleontology. It is an explanation for the staggering diversity of Earth’s five million or more living species. Evolution has several facets. The first is the theory that all living species are the modified descendants of earlier species, and that we all share a common 2) ___ in the distant past. All species are therefore related via a vast tree of life. The second is that this evolution is driven by a process of natural selection or the – survival of the fittest.
3) ___ argued that all individuals struggle to survive on limited resources, but some have small, heritable differences that give them a greater chance of surviving or reproducing, than individuals lacking these beneficial traits. Such individuals have a higher evolutionary fitness, and the useful traits they possess become more common in the population because more of their offspring survive. Eventually these advantageous traits become the norm. Conversely, harmful traits are quickly eradicated as individuals that possess them are less likely to reproduce. Natural selection therefore works to create a population that is highly suited to its environment, and can adapt to changes.
Evolution is the process of change in all forms of life over generations, and evolutionary biology is the study of how evolution occurs. Life evolves by means of mutations (changes in an organism’s hereditary information), 4) ___ drift (random change in the genetic variation of a population from generation to generation), and natural selection (the non-random and gradual process of natural variation by which observable traits (such as eye color) become more or less common in a population). All individuals have hereditary material in the form of genes that are received from their 5) ___, then passed on to their offspring. Among offspring there are variations of genes due to the introduction of new genes via random changes called mutations or via reshuffling of existing genes during sexual 6) ___. The offspring differs from the parent in minor random ways. If those differences are helpful, the offspring is more likely to survive and reproduce. This means that more offspring in the next generation will have that helpful difference. Not all individuals will not have equal chances of reproductive success. In this way, traits that result in organisms being better adapted to their living conditions become more common in descendant populations. These differences accumulate resulting in changes within the population. This process is responsible for the many diverse life forms in the world.
The forces of evolution are most evident when populations become isolated, either through geographic distance or by other mechanisms that prevent genetic exchange. Over time, isolated populations can branch off into new 7) ___. The majority of genetic mutations neither assist, change the appearance of, nor bring harm to individuals. Through the process of genetic drift, these mutated genes are neutrally sorted among populations and survive across generations by chance alone. In contrast to genetic 8) ___, natural selection is not a random process because it acts on traits that are necessary for survival and reproduction. Natural selection and random genetic drift are constant and dynamic parts of life and over time this has shaped the branching structure in the tree of life.
The modern understanding of evolution began with the 1859 publication of Charles Darwin’s On the 9) ___ of Species. In addition, Gregor Mendel’s work with plants helped to explain the hereditary patterns of genetics. Fossil discoveries in paleontology, advances in population genetics and a global network of scientific research have provided further details into the mechanisms of evolution. Scientists now have a good understanding of the origin of new species (speciation) and have observed the speciation process in the laboratory and in the wild. 10) ___ is the principal theory that biologists use to understand life and is used in many disciplines, including medicine, psychology, conservation, biology, forensics, anthropology, agriculture and other social-cultural applications.
ANSWERS: 1) selection; 2) ancestor; 3) Darwin; 4) genetic; 5) parents; 6) reproduction; 7) species; 8) drift; 9)Origin; 10) Evolution
Charles Darwin Suffered From Various Gastrointestinal Illnesses (1809-1882)
Doctors Investigate Long Illness and Death of Scientist Known as ?Father of Evolution’
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. In modified form, Darwin’s scientific discovery is the unifying theory of the life sciences, explaining the diversity of life.
Two hundred years after the birth of Charles Darwin, the father of evolution, doctors are putting modern medicine to the test to unravel the mystery of the painful illness that plagued the scientist for much of his life. Darwin was the subject of one of the Historical Clinicopathological Conferences (CPC) sponsored by the University of Maryland School of Medicine and the Veterans Affairs (VA) Maryland Health Care System. This conference was devoted to the modern medical diagnosis of disorders that affected the great Charles Darwin, known to everyone as the Father of Evolution.
Darwin was born in England on February 12, 1809. He suffered from chronic vomiting, abdominal pain and gastrointestinal distress for much of his life, all while maintaining his career as an incredibly influential scientist and fathering 10 children. A naturalist, traveling the world cataloging and observing wildlife and fossils, Darwin became fascinated by the way species seemed to adapt and change. It was in 1859 that he published his seminal work, On the Origin of Species, detailing his theory of evolution and natural selection. He went on to describe the evolution of humans and sexual selection in later books, and he also published on plants and geology. His work changed the way the world regarded science and serves as the foundation for the field of evolution. Darwin died of heart failure in 1882 at the age of 73.
Now, two centuries after his birth, the Historical Clinicopathological Conference examined both the illness that affected him for much of his life and the heart failure that led to his death. The physician taking up Darwin’s case was noted gastroenterologist Sidney Cohen, M.D., professor of medicine and director of research at the Jefferson Medical College of Thomas Jefferson University in Philadelphia. Each year at the conference, a medical expert is joined by a historian who summarizes the life and historical impact of the figure in question. Organizers have taken a different avenue to put Darwin’s life into perspective: A guest speaker at this conference was Ruth Padel, Ph.D., an award-winning poet and writer who also is Darwin’s great-great-granddaughter. Dr. Cohen said he has never taken up a case quite like Darwin’s. This case is quite unusual in that there is no physical evidence – no x-rays, no blood studies. This is purely a symptom-based assessment, an analysis of this journey of invalidism that he suffered throughout his life, said Dr. Cohen. Darwin’s lifelong history does not fit neatly into a single disorder based historically only upon symptom assessment, he added. I make the argument that Darwin had multiple illnesses in his lifetime.
Careful review of the details of Darwin’s life and health helped Dr. Cohen reach three conclusions about the scientist’s health and ailments. He believes that Darwin suffered from cyclic vomiting syndrome, which was the dominant illness early in his life. Cyclic vomiting syndrome is a condition characterized by a collection of symptoms, mainly patterns of chronic vomiting.
Darwin led a relatively healthy young life until his late 20s. He left home at 22 to travel the globe for the next five years, collecting biological specimens in areas such as South America, the Pacific, the Far East and Africa. He remained healthy for more than a year after returning from his trip. It was then that his symptoms began. His disorder included sudden attacks of abdominal pain, nausea, vomiting and retching, described as gastric flatus. When the symptoms were at their worst, he vomited after nearly every meal. He seldom vomited food, just stomach acid and other secretions, and his weight and nutrition remained normal. The symptoms match up with those of cyclic vomiting syndrome, says Dr. Cohen. The gastroenterologist also believes Darwin suffered from a parasitic illness called Chagas disease, which he most likely contracted during his five years traveling the globe on the HMS Beagle. Chagas symptoms often lay dormant for years, as they seem to have done with Darwin. Chagas would describe the heart disease, cardiac failure or ?degeneration of the heart’ – the term used in Darwin’s time to mean heart disease – that he suffered from later in life and that eventually caused his death, explained Dr. Cohen.
Dr. Cohen has an additional explanation for his abdominal pain and gastrointestinal distress. He believes the scientist also suffered from Helicobacter pylori, the bacteria that cause peptic ulcer disease. H. pylori and Chagas disease can be contracted in the same areas of the world and often occur together, the doctor said. Physicians of his time diagnosed Darwin with dozens of conditions, including schizophrenia, appendicitis, lead poisoning and lactose intolerance. He was treated with cures of the day, including arsenic, hydrotherapy, aloes, strychnine and codeine, which provided at most temporary relief. Unfortunately, doctors practicing in Darwin’s lifetime would not have known about the conditions Dr. Cohen has diagnosed, and would not have had access to our modern treatments. For the most part, none of these illnesses were described during Darwin’s lifetime, said Dr. Cohen.
It is particularly poignant that the scientists and physicians of his time could not provide Darwin, the father of modern life sciences, with relief from the ailments that affected so much of his life, said Philip A. Mackowiak, M.D., M.B.A., professor and vice chair of the Department of Medicine of the University of Maryland School of Medicine and Chief of the Medical Care Clinical Center of the VA Maryland Health Care System. Dr. Mackowiak founded the annual CPC in 1995. This is precisely the type of historically significant mystery the CPC seeks to unravel. We hope examination of this case adds to the understanding and appreciation of this great man, who was able to accomplish so much despite his medical condition. Dr. Cohen said his respect for Darwin grew the more he learned about the man. Darwin was born on the same day as Abraham Lincoln in 1809. That these two men born on that same day have such a lasting impact on our world 200 years later is extraordinary. I have tremendous admiration for Darwin.
Diagnosis by (Dr. Sidney Cohen): Cyclic vomiting syndrome
Alterative Diagnosis: Hypochondriasis
Young Charles Darwin
Charles Darwin, age 51
Structured Physical Activity Program Can Help Maintain Mobility in Vulnerable Older People
Older people who lose their mobility have higher rates of disease, disability, and death. A substantial body of research has shown the benefits of regular physical activity for a variety of populations and health conditions. But none has identified a specific intervention to prevent mobility disability.
According to an article published online in the Journal of the American Medical Association (27 May 2014), a carefully structured, moderate physical activity program can reduce risk of losing the ability to walk without assistance, perhaps the single most important factor in whether vulnerable older people can maintain their independence.
In this large clinical study, it was found that a regular, balanced, and moderate physical activity program followed for an average of 2.6 years, reduced the risk of major mobility disability by 18% in an elderly, vulnerable population. Participants receiving the intervention were better able to maintain their ability to walk without assistance for 400 meters, or about a quarter of a mile, the primary measure of the study. Results of the large clinical trial, was conducted by researchers at the University of Florida, Gainesville and Jacksonville, and colleagues at seven other clinics across the country.
The Lifestyle Interventions and Independence for Elders (LIFE) trial included 1,635 sedentary men and women aged 70-89 at risk of disability, who were randomly assigned to a program of structured, moderate-intensity physical activity or to a health education program focused on topics related to successful aging. The diverse participants were recruited from urban, suburban, and rural communities. The study was also conducted at field sites at Northwestern University in Chicago; Pennington Biomedical Research Center in Baton Rouge, Louisiana; Stanford University in Palo Alto, California; Tufts University in Boston; the University of Pittsburgh; Wake Forest University in Winston-Salem, North Carolina; and Yale University in New Haven, Connecticut. Data management and analysis were coordinated by Wake Forest University.
Participation in the study averaged 2.6 years. The physical activity group of 818 people gradually worked up to the goal of 150 minutes of weekly activity, including 30 minutes of brisk walking, 10 minutes of lower extremity strength training, 10 minutes of balance training, and large muscle flexibility exercises. Their programs took place at a clinic twice a week and at home three or four times a week. The 817 people in the comparison group participated in weekly health education workshops for the first 26 weeks, followed by monthly sessions thereafter. They also performed five to 10 minutes of upper body stretching and flexibility exercises in each session. Participants in both groups were assessed every six months at clinic visits.
Adherence to the program was measured by attendance at sessions and by questionnaires in which participants recorded the number of hours per week that they were physically active. In addition, participants’ activity was recorded for one week during each year of the trial through an accelerometer, a small belt device that measures physical activity.
According to the authors, at the beginning of this trial, all the participants were at high risk for mobility disability, but were able to walk about a quarter of a mile without a cane, walker, or help of another person. But they did have sedentary lifestyles and low scores on some standard physical tests that measure risk for disability. The study showed it is never too late for exercise to have a positive effect for a significant portion of frail older people. The authors also noted that participants attended more sessions and stayed in the study longer than anticipated, and that the people in the intervention group were very enthusiastic about the exercise program.
In 2011, NIA launched Go4Life, a national exercise and physical activity campaign, based on previously demonstrated benefits of exercise for healthy community-dwelling adults age 50 and older. The LIFE study adds to that evidence with findings that older people vulnerable to disability can also be included among those who could reap rewards from regular physical activity. Go4Life emphasizes endurance, strength, flexibility, and balance exercises. For additional information, go to http://www.nia.nih.gov/go4life.
Blood Pressure and Incidence of 12 Cardiovascular Diseases: Lifetime Risks, Healthy Life-Years Lost, and Age-Specific Associations in 1.25 Million People
The associations of blood pressure with the different manifestations of incident cardiovascular disease in a contemporary population have not been compared. According to an article published in The Lancet (2014;383:1899-1911), a study was performed to analyze the associations of blood pressure with 12 different presentations of cardiovascular disease.
The study used linked electronic health records from 1997 to 2010 in the CALIBER (CArdiovascular research using linked bespoke studies and electronic health records) program to assemble a cohort of 1.25 million patients, 30 years of age or older and initially free from cardiovascular disease, a fifth of whom received blood pressure-lowering treatments. Heterogeneity was studied in the age-specific associations of clinically measured blood pressure with 12 acute and chronic cardiovascular diseases, and estimated the lifetime risks (up to 95 years of age) and cardiovascular disease-free life-years lost adjusted for other risk factors at index ages 30, 60, and 80 years.
During 5.2 years median follow-up, the study recorded 83,098 initial cardiovascular disease events. In each age group, the lowest risk for cardiovascular disease was in people with systolic blood pressure of 90-114 mm Hg and diastolic blood pressure of 60-74 mm Hg, with no evidence of a J-shaped increased risk at lower blood pressures. The effect of high blood pressure varied by cardiovascular disease endpoint, from strongly positive to no effect. Associations with high systolic blood pressure were strongest for intracerebral hemorrhage (hazard ratio 1.44), subarachnoid haemorrhage (1.43), and stable angina (1.41), and weakest for abdominal aortic aneurysm (1.08).
Compared with diastolic blood pressure, raised systolic blood pressure had a greater effect on angina, myocardial infarction, and peripheral arterial disease, whereas raised diastolic blood pressure had a greater effect on abdominal aortic aneurysm than did raised systolic pressure. Pulse pressure associations were inverse for abdominal aortic aneurysm (HR per 10 mm Hg = 0.91) and strongest for peripheral arterial disease (1.23). People with hypertension (blood pressure >140/90 mm Hg or those receiving blood pressure-lowering drugs) had a lifetime risk of overall cardiovascular disease at 30 years of age of 63.3% compared with 46.1% for those with normal blood pressure; and developed cardiovascular disease 5.0 years earlier. Stable and unstable angina accounted for most (43%) of the cardiovascular disease-free years of life lost associated with hypertension from index age 30 years, whereas heart failure and stable angina accounted for the largest proportion (19% each) of years of life lost from index age 80 years.
According to the authors, the widely held assumptions that blood pressure has strong associations with the occurrence of all cardiovascular diseases across a wide age range, and that diastolic and systolic associations are concordant, are not supported by the findings of this high-resolution study. Despite modern treatments, the lifetime burden of hypertension is substantial and the findings emphasize the need for new blood pressure-lowering strategies.
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FDA’s Final Guidance on Expedited Drug Approvals: Fueling Innovation and Helping Patients
The following is abstracted from FDA Voice (May 29, 2014)
In recent years, there have been important advances to ensure therapies for serious conditions are approved and available to patients as soon as there is sufficient data to show that the therapies’ benefits outweigh their risks. Despite the progress, there is much more work to be done.
The FDA is committed to actively scrutinize, strengthen and streamline the regulatory processes at various steps along the path from drug discovery to delivery – including the clinical development phase, the longest and most expensive period of drug development. As part of this effort, FDA has developed and successfully used a number of flexible and innovative approaches to expedite the development and review of drugs.
Four programs that facilitate and expedite development and review of new drugs that address unmet medical needs in the treatment of serious or life threatening conditions have been especially noteworthy. A look at recent drug approvals suggests that these programs have played an important role in bringing innovative drugs to market. Nearly half of the 27 novel drugs approved by FDA last year took advantage of at least one of these expedited drug development and review approaches. And review times were as short as 4.5 months.
After incorporating input we received from stakeholders to a draft version, FDA has issues a Guidance to Industry on Expedited Programs for Serious Conditions – Drugs and Biologics, in order to provide a more detailed explanation of these programs and help drug innovators determine whether their products are likely candidates. These expedited programs include:
Fast track designation: Providing for more frequent meetings and communications with FDA to discuss the drug’s development plan and ensure collection of appropriate data needed to support drug approval, including such things as the design of the proposed clinical trials and use of biomarkers.
Accelerated Approval: Basing approval not on a clinical endpoint but on an agreed upon surrogate marker, that is a measure such as blood test or urine marker, that is believed to be indicative of a disease state and treatment effect, but not demonstrative of a direct health gain to the patient.
Priority review: Acting on drug applications within 6 months instead of 10 months for standard review, and;
Breakthrough Therapy Designation: Providing all of the benefits of Fast Track designation plus intensive guidance on an efficient drug development program, beginning as early as Phase 1, and the commitment from FDA’s review staff, including senior managers, to work closely together throughout the drug development and review process.
Breakthrough Therapy Designation, created as part of the 2012 FDA Safety and Innovation Act (FDASIA) has been a virtual overnight success. As of May 5, 2014, FDA has received 186 requests for the designation, and granted 48. Six drugs have been approved, including a late-stage lung cancer drug that was approved – four months ahead of its goal date, using evidence from a trial with 163 patients.
Since its inception in 1992, more than 80 new products have been approved under the Accelerated Approval pathway. It has long been successful in driving innovation in cancer and HIV therapies, but we’re encouraging its broader application in other areas, helped by FDASIA which clarified that FDA has the authority to consider epidemiologic, pharmacologic or other evidence developed using biomarkers or other scientific methods or tools in determining whether an endpoint can support accelerated approval.
It’s important to note that FDA’s regulatory flexibility is likely reducing the number of sponsors that avail themselves of the accelerated approval program. Sponsors of most of the recent new drug approvals for rare diseases – products that might otherwise qualify for the accelerated approval program – aren’t opting for that development pathway simply because they don’t need to do so. While all are being approved based on surrogate or intermediate clinical endpoints, most of these products are receiving traditional approvals – meaning that no additional trials will be needed to verify clinical benefit. That’s because FDA has decided that the results were already strong enough.
FDA is urging drug developers and others interested in this movement to take a close look at final guidance, since for those drugs that qualify, participating in one of these expedited programs can reduce the time and possibly the cost of developing new therapies. That’s a win for drug innovation and for patients. Janet Woodcock, M.D., is the Director of FDA’s Center for Drug Evaluation and Research
Pineapple Curry Shrimp with or without Scallops
©Joyce Hays, Target Health Inc.
Anticipating, warm then hot, climate-change weather, in New York, I want to be ready with some tasty but quick and easy meals, so that a lot of time is not spent in the warmest room, the kitchen.
Shrimp and scallops cook very quickly, so I’m experimenting with them first. All you need is fresh seafood (their juices infuse well with the other ingredients) good extra virgin olive oil, garlic, fresh pineapple, cumin, turmeric and chopped cilantro or parsley (or both) and the results are beyond delicious.
1/3 cup extra virgin olive oil, or more as needed
4 to 6 big cloves garlic, cut into slivers
1 1/2 to 2 pounds shrimp, 20 to 30 per pound, peeled, rinsed, and dried. (ask that they be cleaned and de-veined by your fish market)
1/2 lb scallops (optional) clean, dry, then slice and cook with shrimp
Salt and freshly ground black pepper (to your taste)
1 teaspoon ground cumin
1 teaspoon coriander
1 teaspoon chopped fresh ginger
1/2 teaspoon black mustard seed (optional)
1 Tablespoon fresh parsley, chopped (same some for garnish) 1Tablespoon fresh cilantro, chopped (save some for garnish)
1 or 2 cups fresh pineapple (fresh is much better than canned)
Cooking the garlic, spices and herbs ©Joyce Hays, Target Health Inc.
Warm the olive oil in a large, broad ovenproof skillet or heatproof baking pan over low heat. There should be enough olive oil to cover the bottom of the pan; don’t skimp. Add the garlic slivers and cook until garlic turns golden, a few minutes.
First experiment, cooking shrimp, scallops in oil, spices, herbs ©Joyce Hays, Target Health Inc.
Raise the heat to medium-high and add pinch salt and pepper, the cumin and turmeric and all of the spices and herbs. Stir to blend.
Now, add shrimp (and optional scallops) and continue to cook, shaking the pan once or twice and turning the shrimp once or twice, until they are golden brown all over and the mixture is bubbly, 5 to 7 minutes. Do not overcook or the seafood will be rubbery.
Just before serving, add the fresh pineapple to the hot seafood and stir just to warm it up
Garnish with lemon and/or herbs and serve immediately.
©Joyce Hays, Target Health Inc.
We both loved this recipe. I experimented a lot with it, so we ate it more than once or twice. I played around with the spices and the amount of pineapple. By the last try, I added 2 cups pineapple and more spices. However, I would say that if you don’t like very spicy curry, take it easy and taste as you go to get the exact amount of spicyness customized to your taste. I considered adding chopped peanuts and coconut for a more Thai dish, but decided to wait and do that another time.
The pineapple curry shrimp was served on a saffron jasmine rice dish that I created with golden raisins and toasted pine nuts (will give recipe at later date) and sauteed garlic broccoli. At the bottom of our wine cooler we found another bottle of ice cold Antinori Orvieto which we consumed with pleasure. A perfect wine for seafood and for curry dishes. We recommend everything about this menu to our readers.
Over the weekend we saw Broadway’s revival, Raisin in the Sun. Wonderful production! The power of Denzel is revealed by all of the limited run performances, being sold out. We got our tickets long before they became publicly available.
Ice cold Orvieto – delicious! ©Joyce Hays, Target Health Inc.
Hope your weekend went well, was relaxing and rejuvenating!
Bon Appetit !