Risk-Based Trial Management/Monitoring Conference


CBI’s Risk-Based Trial Management and Monitoring Conference is just TWO weeks away! Join your peers, thought-leaders and trial counterparts to collaborate on the growing challenges and solutions for ensuring RBM data quality. Learn how to reduce the complexity of implementing an efficient RBM methodology, system adoption, process integration and much more! Visit www.cbinet.com/RBM to view the full conference agenda.


RBM Risk Assessment ? What are, and how to mitigate the risks from the patient, study, site and sponsor perspectives? – Presented by Dr. Jules T. Mitchel, President, Target Health Inc.


Assessing risk is an ongoing process for any industry, and clearly the impact of all risks are not equal. In the clinical research environment, the primary concern is the safety risk to the patient when taking an experimental medicinal product or using an unapproved medical device. Other risks include the impact of not following the protocol and not being complaint with rules and regulations. This session presents a model for risk assessment and provides concrete examples. Risk mitigation:


1. Identify risk factors

a) the severity of the event, should it happen

b) the likelihood that the event would happen

c) the likelihood of detecting the event

2. Risk mitigation strategies for each risk

3. Assessment of unique risks associated with specific studies

4. A model is presented with examples


For more information about Target Health contact Warren Pearlson (212-681-2100 ext. 165). For additional information about software tools for paperless clinical trials, please also feel free to contact Dr. Jules T. Mitchel. 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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Scientists Develop Human Embryos Through Early Post-implantation Stages

Human embryo, 8-9 weeks, 38 mm. Graphic credit: Anatomist90 – Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=18327186


Editor’s note: These embryos under study were the result of egg collection and fertilization during IVF procedures.  In this procedure, often 8+ eggs are collected and fertilized. Since there is a limit as to the number of fertilized eggs that can be implanted, all excess fertilized eggs are normally destroyed. In the UK, embryos can be studied up to 14 days post fertilization.


Last year, research enabled a new technique that allows embryos to develop in vitro beyond the implantation stage (when the embryo would normally implant into the womb). This technique has been developed by scientists at the University of Cambridge allowing them to analyze for the first time, key stages of human embryo development up to 13 days after 1) ___. The technique could open up new avenues of research aimed at helping improve the chances of success of IVF.


Once an egg has been fertilized by a 2) ___, it divides several times to generate a small, free-floating ball of stem cells. Around day three, these stem cells cluster together inside the embryo towards one side; this stage is known as the blastocyst. The blastocyst comprises three cell types: cells that will develop into the future body (which form the ‘epiblast’), cells that will develop into the placenta and allow the embryo to attach to the womb, and cells that form the primitive endoderm that will ensure that the fetus’s organs develop properly and will provide essential nutrients. This pre-implantation period — so-called as the blastocyst has yet to implant itself into the 3) ___ — has been extensively studied in human embryos using in vitro culture methods. However, on the seventh day of development, the human embryo must implant into the uterus of the mother to survive and to develop further, even though UK law permits embryos to be studied in the laboratory for up to 14 days. The failure of an embryo to implant is a major cause of early pregnancy loss and yet the cellular and molecular changes that take place in the human embryo at this stage remain unknown. This is because it is impossible to carry out such studies on embryos developing in the womb, and until now there has been no system to culture human embryos in the laboratory beyond day seven.


According to 2 papers published in Nature and Nature Cell Biology, reported the development of a technique that allows them to culture 4) ___ embryos outside the body of the mother for an additional six days, up to day 13 of development. Using the technique, the researchers have shown that the reorganization of the embryo that normally takes place during early post-implantation development can be achieved in the lab given the right culture conditions. According to the authors, “implantation is a milestone in human development as it is from this stage onwards that the embryo really begins to take shape and the overall body plans are decided. It is also the stage of 5) ___ at which many developmental defects can become acquired. But until now, it has been impossible to study this in human embryos. This new technique provides a unique opportunity to get a deeper understanding of our own development during these crucial stages and help us understand what happens, for example, during miscarriage.“


The authors established a system for the in vitro culture of human embryos and, using this technique, followed the development of the embryos up to day 13 of development. Immediately following ‘implantation’, the three cell types that comprise the 6) ___ reorganize into a new configuration. According to the authors, “The stem cells in the epiblast that will form the future body have the remarkable ability to self-organize themselves and create a cavity that represents the basic structure of the early post-implantation human embryo and that without this cavity, it would be impossible for the embryo to develop further. It is also a mechanism that we can study using human embryonic stem 7) ___.“ This cavity was previously thought to arise through a process known as apoptosis, or programmed cell 8) ___, but using human embryonic stem cell models, the authors were able to show that in fact cell death is not required for the cavity formation in human embryos. This process is similar to what we have recently observed in mouse embryos, despite the significant differences in the structure of post-9) ___ embryos in these different mammalian species, and suggests it may be a fundamental process conserved across many species. This research has been possible thanks to couples that underwent IVF treatment and decided to donate their surplus 10) ___ to advance our understanding of the early phases of post-implantation human development.


The research was licensed by the UK Human Fertilization and Embryology Authority.

Source: University of Cambridge. The original story is licensed under a Creative Commons Attribution 4.0 International License.  Journal References: Nature Cell Biology, 2016; DOI: 10.1038/ncb3347; Nature, 2016; DOI: 10.1038/nature17948


Embryology: Excellent animation


ANSWERS: 1) fertilization; 2) sperm; 3) uterus; 4) human; 5) pregnancy; 6) blastocyst; 7) cells; 8) death; 9) implantation; 10) embryos



A study of embryos by Leonardo da Vinci. Graphic credit: – Hi! Magazine (direct link), Public Domain, https://commons.wikimedia.org/w/index.php?curid=42138639


In humans, the term embryo refers to the ball of dividing cells from the moment the zygote implants itself in the uterus wall until the end of the eighth week after conception. Beyond the eighth week after conception (tenth week of pregnancy), the developing human is then called a fetus.


Aristotle’s On the Generation of Animals is referred to in Latin as De Generatione Animalium. As with many of Aristotle’s writings, the exact date of authorship is unknown, but it was produced in the latter part of the fourth century BCE. This book is the second recorded work on embryology as a subject of philosophy, being preceded by contributions in the Hippocratic corpus by about a century. It was, however, the first work to provide a comprehensive theory of how generation works and an exhaustive explanation of how reproduction works in a variety of different animals. As such, De Generatione was the first scientific work on embryology. Its influence on embryologists, naturalists, and philosophers in later years was profound. Among these were Hieronymus Fabricius, William Harvey, St. Thomas Aquinas, and Charles Darwin.


A brief overview of the general theory expounded in De Generatione requires an explanation of Aristotle’s philosophy. The Aristotelian approach to philosophy is teleological, and involves analyzing the purpose of things, or the cause for their existence. These causes are split into four distinct types: final cause, formal cause, material cause, and efficient cause. The final cause is what a thing exists for, or its ultimate purpose. The formal cause is the definition of a thing’s essence or existence, and Aristotle states that in generation, the formal cause and the final cause are similar to each other, and can be thought of as the goal of creating a new individual of the species. The material cause is the stuff a thing is made of, which in Aristotle’s theory is the female menstrual blood. The efficient cause is the “mover“ or what causes the thing’s existence, and for reproduction Aristotle designates the male semen as the efficient cause. Thus, while the mother’s body contains all the material necessary for creating her offspring, she requires the father’s semen to start and guide the process.


De Generatione consists of five books, each containing multiple chapters. Books I and II are of most interest to embryology. Book III is a comparative study of zoology that applies principles from Book II to distinct species of animals. Book IV contains miscellaneous information about aspects of reproduction, such as how heredity works and birth defects occur. Book V compares the characteristics that all animals share, and is primarily a discussion of sensory organs and the physical appearance of animals, focusing on characteristics like hair, coloration, voice, and teeth. Aristotle’s research and writing, influenced Renaissance scholars. Early studies of embryology came from the work of the Italian anatomists Aldrovandi, Aranzio, Leonardo da Vinci, Marcello Malpighi, Gabriele Falloppio, Girolamo Cardan, Emilio Parisian, Fortunio Licata, Stefano Lorentzian, Spallanzani, Enrico Sertoli, and Mauro Rossini.


Editor’s note: Dear Readers, it’s not clear to us, how Aristotle’s theories of epigenesis became temporarily derailed by the ideas of preformation. We’re guessing it was the prevailing notions of the church. If any reader has more specific knowledge, we would appreciate an email, clearing up this approximately, 150-year gap, when Aristotle’s ideas were eschewed.


By the 18th century, the prevailing notion in western human embryology was preformation: the idea that semen contains an embryo – a preformed, miniature human, or homunculus – that was planted in the female during intercourse, which then grew into a larger being, as it developed during pregnancy. The competing explanation of embryonic development was epigenesis, originally proposed 2,000 years earlier by Aristotle. However, during the late 18th century an extended and controversial debate among biologists finally led epigenesis to eclipse the short-lived, but established preformationist view. According to epigenesis, the form of an animal emerges gradually from a relatively formless egg. As microscopy improved during the 19th century, biologists could see that embryos took shape in a series of progressive steps, and epigenesis displaced preformation as the favored explanation among embryologists.


After 1827: Karl Ernst von Baer and Heinz Christian Pander proposed the germ layer theory of development; von Baer discovered the mammalian ovum in 1827. Modern embryological pioneers include Charles Darwin, Ernst Haeckel, J.B.S. Haldane, and Joseph Needham. Other important contributors include William Harvey, Kaspar Friedrich Wolff, Heinz Christian Pander, August Weismann, Gavin de Beer, Ernest Everett Just, and Edward B. Lewis.


After the 1950s, with the DNA helical structure being unraveled knowledge increased in the field of molecular biology, and developmental biology emerged as a field of study which attempts to correlate the genes with morphological change, and so tries to determine which genes are responsible for each morphological change that takes place in an embryo, and how these genes are regulated. So, here in the 21st Century, we can acknowledge the genius of Hippocrates and Aristotle, whose correct observations many centuries ago, prevail. Those ancient Greeks knew a thing or two. Sources: Wikipedia; nih.govasu.edu.


Healthy Lifestyle Reduces Heart Attack, Stroke Risk After Gestational Diabetes


Gestational diabetes is a type of diabetes, or high blood sugar, that occurs only during pregnancy. Although it often disappears after birth, many women who had the condition later develop type 2 diabetes, usually by middle age. Some studies have shown women who had gestational diabetes are also at risk for cardiovascular disease, such as high blood pressurehigh blood cholesterolhardening of the arteriesheart attack and stroke.


According to an article published online in JAMA Internal Medicine (October 16, 2017), women who have had gestational diabetes may be able to reduce or even eliminate their risk for cardiovascular disease by following a healthy lifestyle in the years after giving birth. For the study, data were analyzed from the Nurses’ Health Study II (NHS II), following health habits and medical history of more than 90,000 women from before pregnancy through middle age and the early senior years. NHS II is an observational cohort study of US female nurses established in 1989, with ongoing follow-up. Biennial questionnaires updated behavioral characteristics, health outcomes, and lifestyle factors. Those included in the analysis reported at least 1 pregnancy and were free of CVD and cancer at baseline. Follow-up through May 31, 2015, was complete for more than 90% of eligible participants. The study confirmed the links between gestational diabetes and cardiovascular disease found by other studies. It also provides some of the strongest evidence to date that cardiovascular disease after gestational diabetes isn’t inevitable for women who adopt a healthy diet, maintain a healthy weight, exercise moderately and do not smoke. Results showed that women who failed to adopt a healthy lifestyle in the wake of gestational diabetes had a 43%-higher risk for cardiovascular disease, particularly heart attack and stroke.


Immune System May Mount an Attack In Parkinson’s Disease


Parkinson’s disease (PD) is a neurodegenerative disorder in which dopamine-producing brain cells die off, resulting in tremors, muscle stiffness, loss of balance and slow movement. Additional symptoms may include emotional changes and disrupted sleep. According to an article published online in Nature (June 21, 2017A), a new study suggests that T cells, which help the body’s immune system recognize friend from foe, may play an important role in PD.


For the study, the authors collected blood samples from 67 individuals with PD and 36 healthy controls. Immune cells were extracted from the samples and mixed with portions of the alpha-synuclein protein, which accumulates in the brains of people with PD and can result in cell death. Results that T cells from people with PD responded to the presence of alpha-synuclein to a much greater degree than those gathered from the control group. In particular, two regions of alpha-synuclein evoked reactions from T cells: a section that often contains mutations linked with PD, and a portion undergoing a chemical change that can lead to accumulation of the protein in the brain. The authors identified four genetic variations that were associated with T cell reactivity to alpha-synuclein. More than half of people with PD carried at least one of those variants, compared to 20% of controls.


According to the authors, these findings expose a potential biomarker for PD that may someday help in diagnosing the disease or be used to evaluate how well treatments are working. The authors added that the results also suggest that PD may have characteristics of an autoimmune disease, in which the immune system incorrectly attacks the body’s own cells.


FDA Approves CAR-T Cell Therapy to Treat Adults with Certain Types of Large B-Cell Lymphoma


Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma (NHL) in adults. NHLs are cancers that begin in certain cells of the immune system and can be either fast-growing (aggressive) or slow-growing. Approximately 72,000 new cases of NHL are diagnosed in the U.S. each year, and DLBCL represents approximately one in three newly diagnosed cases.


The FDA has approved Yescarta (axicabtagene ciloleucel), a cell-based gene therapy, to treat adult patients with certain types of large B-cell lymphoma who have not responded to or who have relapsed after at least two other kinds of treatment. Yescarta, a chimeric antigen receptor (CAR) T cell therapy, is the second gene therapy approved by the FDA and the first for certain types of non-Hodgkin lymphoma (NHL).


According to FDA, this approval marks another milestone in the development of a whole new scientific paradigm for the treatment of serious diseases, and that in just several decades, gene therapy has gone from being a promising concept to a practical solution to deadly and largely untreatable forms of cancer. FDA added that it will soon release a comprehensive policy to address how we plan to support the development of cell-based regenerative medicine. That policy will also clarify how we will apply our expedited programs to breakthrough products that use CAR-T cells and other gene therapies.


Yescarta is approved for use in adult patients with large B-cell lymphoma after at least two other kinds of treatment failed, including DLBCL, primary mediastinal large B-cell lymphoma, high grade B-cell lymphoma and DLBCL arising from follicular lymphoma. Yescarta is not indicated for the treatment of patients with primary central nervous system lymphoma. Each dose of Yescarta is a customized treatment created using a patient’s own immune system to help fight the lymphoma. The patient’s T-cells, a type of white blood cell, are collected and genetically modified to include a new gene that targets and kills the lymphoma cells. Once the cells are modified, they are infused back into the patient. The safety and efficacy of Yescarta were established in a multicenter clinical trial of more than 100 adults with refractory or relapsed large B-cell lymphoma. The complete remission rate after treatment with Yescarta was 51%.


Treatment with Yescarta has the potential to cause severe side effects. It carries a boxed warning for cytokine release syndrome (CRS), which is a systemic response to the activation and proliferation of CAR-T cells causing high fever and flu-like symptoms, and for neurologic toxicities. Both CRS and neurologic toxicities can be fatal or life-threatening. Other side effects include serious infections, low blood cell counts and a weakened immune system. Side effects from treatment with Yescarta usually appear within the first one to two weeks, but some side effects may occur later. Because of the risk of CRS and neurologic toxicities, Yescarta is being approved with a risk evaluation and mitigation strategy (REMS), which includes elements to assure safe use (ETASU). The FDA is requiring that hospitals and their associated clinics that dispense Yescarta be specially certified. As part of that certification, staff involved in the prescribing, dispensing or administering of Yescarta are required to be trained to recognize and manage CRS and nervous system toxicities. Also, patients must be informed of the potential serious side effects and of the importance of promptly returning to the treatment site if side effects develop.


To further evaluate the long-term safety, the FDA is also requiring the manufacturer to conduct a post-marketing observational study involving patients treated with Yescarta.


The FDA granted Yescarta Priority Review and Breakthrough Therapy designations. Yescarta also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases. The Yescarta application was reviewed using a coordinated, cross-agency approach. The clinical review was conducted by the FDA’s Oncology Center of Excellence, while CBER conducted all other aspects of review and made the final product approval determination.


The FDA granted approval of Yescarta to Kite Pharma, Inc.


Celebrating Diwali, Especially the Fourth Day, Called Diwali Padva Dedicated to Wife – Husband Relationships


Diwali is the five day Hindu-Buddhist festival of lights celebrated every year in Autumn in the northern hemisphere (spring in southern hemisphere). It spiritually signifies the victory of light over darkness, good over evil, knowledge over ignorance, and hope over despair. In the Gregorian calendar, Diwali falls between mid-October and mid-November. With the celebratory explosion of lights, there is a certain similarity between Diwali, Hanukkah, and Christmas. Diwali holiday encourages interfaith participation, which is a welcome aspect of any religion in the 21st Century.


Your executive chef, looked over dozens and dozens of recipes, deemed appropriate for this great Diwali celebration. I then adapted them, to our taste. Some, like the one above, which I am calling Peppers Galore, are my own creations. Above, are four different colors of peppers, seeded, then cut in strips and laid out on a baking sheet covered with parchment. One red onion was chopped and sprinkled over the peppers. Extra virgin olive oil was sprinkled over these veggies and then roasted in a 450 degree oven for about 15 minutes. Next time, I will add to a small bowl, the olive oil, much more seasoning, juice of 1 fresh lemon, and a Tablespoon of toasted black mustard seeds, which I love. ©Joyce Hays, Target Health Inc.


Here is my version of Dal. Jules and I loved this dish; we particularly liked the combination of this Dal with my version of Vegetable cutlets. We will not wait until another celebration to have this meal again. Dal is enjoyed by Pakistanis and Indians. ©Joyce Hays, Target Health Inc.


My Dal Recipe for Two People


1 cup yellow lentils

1/4 cup butter.

1 and 1/2 cups onion, well chopped.

10 fresh garlic cloves, sliced

2 or more scallions, chopped

1 chili pepper, seeded and minced.

1 teaspoon cumin

1 teaspoon curry

1 teaspoon cardamom

1 teaspoon turmeric

1 pinch salt

1 pinch black pepper

1 teaspoon cinnamon

1 big pinch ground nutmeg, or freshly grated

1 Tablespoon, black mustard seeds, toasted

1 cup pine nuts, toasted

1 cup golden raisins

1 inch fresh ginger, peeled, then finely minced

3 to 4 cups chicken stock or broth

1 bay leaf (remove before serving)

1 cup fresh cilantro, well chopped

1 cup fresh parsley, well chopped

Zest of 1 fresh lemon

Juice of 1 fresh lemon

Extra virgin olive oil for cooking


As you can see most of the ingredients are not in this photo. That’s because this is the first experiment making Dal, where I went by one of the recipes I educated myself with. As I read on and on, it was clear that there were hundreds of versions. At that point, I decided to create my own version, which is below. ©Joyce Hays, Target Health Inc.



1. Do all your cutting, chopping, grating, slicing, so all ingredients are ready to add, while you continue to stir.


Cutting, chopping, slicing all on same board. ©Joyce Hays, Target Health Inc.


2. In glug of olive oil, toast the black mustard seeds and the pine nuts

3. Over medium heat, melt butter in a large pot, and add onions, garlic and scallions. Stir until soft.

4. To the pot, while stirring, add the chili, lentils, ginger, all spices, seasoning and bay leaf. Cook for 1 to 2 minutes.


5. Add the chicken stock, bring to a boil, add all herbs, lemon zest, fresh lemon juice, raisins, toasted mustard seeds, toasted pine nuts, while continuing to stir, then lower flame to a simmer.


6. Cook until lentils are tender, stirring occasionally.



Cover and simmer for about 5 more minutes. ©Joyce Hays, Target Health Inc.


Our Diwali feast for two: Clockwise, starting with the glass bowl of Dal, vegetable cutlets, fresh garden salad, samosas, spicy tomato sauce, chicken, grapes, another variety of samosa. ©Joyce Hays, Target Health Inc.


Left out Peppers Galore, in photo above. See desserts, below. ©Joyce Hays, Target Health Inc.


This is my first attempt at making Kheer, a favorite Pakistani-Indian dessert with dates. ©Joyce Hays, Target Health Inc.


The world needs more celebrating of light over dark, good over evil, knowledge over ignorance and hope over despair. This will not be handed to us. People must have this vision of global cooperation, and work hard to persuade inactive citizens to get out, and vote for it. Equality for all leads to peace and harmony. ©Joyce Hays, Target Health Inc.


From Our Table to Yours

Bon Appetit!