Clinical Trials Transformation Initiative (CTTI)


The Clinical Trials Transformation Initiative (CTTI) is a public private partnership with Duke University and FDA with a mission to develop and drive adoption of practices that will increase the quality and efficiency of clinical trials. Target Health has been a member of the Steering Committee since 2008, and Dr. Mitchel had the honor, between 2014-2015, to sit on the Executive Committee, representing the Steering Committee.


This past week, the Steering Committee met in D.C. with the theme of how to implement CTTI recommendations. It was a very stimulating meeting that included presentations and breakout sessions. Our take-away of the meeting is that it will take leadership and ownership to make the changes needed to completely modernize the clinical trial enterprise. All agreed that we look forward to examples of how CTTI companies are implementing changes.


At Target Health, the impact of CTTI has been in the area of managing clinical trials using principles of Quality by Design, and our approach to risk-based monitoring, based on the publication of the CTTI Monitoring Survey Project: Monitoring the Quality of Conduct of Clinical Trials: A Survey of Current Practices.


Target Health was also a key team member in CTTI’s Registry Trials Recommendations that has provided a pathway for registries to be used for the conduct of more efficient clinical trials, bringing new treatments to patients faster. Registries are data collection tools typically used to better understand long-term trends in a specific population, such as patients with a particular disease or exposure to a certain treatment. However, if designed appropriately, registries can be used as a data source within which clinical trials can be performed. FDA recently signaled a commitment to developing policies regarding the use of registries and other forms of “real-world evidence“ for research, including clinical trials. While registries have long been used to support safety evaluations, their use for efficacy evaluations is a newer practice. CTTI’s recommendations outline best practices for assessing and designing registries so that the data should be able to meet expectations for FDA review of new products. The recommendations can be applied to existing registries or for developing new registries. The goal is to increase the practice of leveraging registries to facilitate high-quality clinical trials at lower costs.


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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Focal Dystonia and MD or Musician’s Dystonia

Focal Dystonia in a pianist. Improvement in one day – YouTube


Focal dystonia is a neurological condition, a type of dystonia, that affects a muscle or group of muscles in a specific part of the body, causing involuntary muscular contractions and abnormal postures. For example, in focal hand dystonia, the 1) ___ either curl into the palm or extend outward without control. In musicians, the condition is called musician’s focal dystonia, or simply, musician’s dystonia. In sports, it is commonly referred to as the yips.


Current medical science does not precisely describe the causes of dystonia. Misfiring of neurons in the sensorimotor cortex, a thin layer of neural tissue that covers the 2) ___, is thought to cause contractions. This misfiring may result from impaired inhibitory mechanisms during muscle contraction. When the brain tells a given muscle to contract, it simultaneously silences muscles that would oppose the intended movement. It appears that dystonia interferes with the brain’s ability to inhibit those surrounding muscles, leading to loss of selectivity. The sensorimotor cortex is organized as discrete “maps“ of the human body. Under normal conditions, each body part (such as individual fingers) occupies a distinct area on these cortical 3) ___. In dystonia, these maps lose their distinct borders and overlap occurs. Exploration of this initially involved over-training particular finger movements, in non-human primates, which resulted in the development of focal hand dystonia.


Examination of the primary somatosensory cortex in the trained animals showed grossly distorted representations of the maps pertaining to the fingers when compared to the untrained animals. Additionally, these maps in the dystonic animals had lost the distinct borders that were noted in the untrained animals. Imaging studies in humans with focal dystonia have confirmed this finding. Also, synchronous afferent stimulation of peripheral muscles induces organizational changes in motor representations, characterized both by an increase in map size of stimulated muscles and a reduction in map separation, as assessed using TMS or 4) ___ ___ ___. The cross-connectivity between areas that are normally segregated in the sensory cortex may prevent normal sensorimotor feedback and so contribute to the observed co-contraction of antagonist muscle groups, and inappropriately timed and sequenced movements that underlie the symptoms of focal dystonia. It is hypothesized that a deficit in inhibition caused by a genetically mediated loss of inhibitory interneurons may be the underlying cause of the deficits observed in 5) ___. While usually painless, in some instances the sustained contraction and abnormal posturing in dystonia cause 6) ___. Focal dystonia most typically affects people who rely on fine motor skills – musicians, writers, surgeons, etc. It is thought that the excessive motor training those skills require may contribute to the development of dystonia as their cortical maps become enlarged and begin to overlap. Focal dystonia is generally “task-specific,“ meaning that it is only problematic during certain activities.


Dystonia is often treated with injections of Botox, a commercially prepared form of botulinum toxin. Botox reduces the symptoms of the disorder but it is not a cure for dystonia. Since the root of the problem is 7) ___, doctors have explored sensorimotor retraining activities to enable the brain to “rewire“ itself and eliminate dystonic movements. The work of several doctors such as Nancy Byl and Joaquin Farias has shown that sensorimotor retraining activities and proprioceptive stimulation can induce neuroplasticity, making it possible for patients to recover substantial function that was lost to focal dystonia. Bass guitarist and instructor Scott Devine said that he wears a glove while playing bass guitar because of the condition. He finds that the glove stops the involuntary finger movements. He says it works for him but does not suggest that it may work for everyone with the condition.


Performing music at a professional level is probably one of the most complex human accomplishments. Extremely fast and complex, temporo-spatially predefined movement patterns have to be learned, memorized, and retrieved with high reliability in order to meet the expectations of listeners. Performing music requires not only the integration of multimodal sensory and motor information, and its precise monitoring via auditory and kinesthetic feedback, but also emotional communicative skills, which provide a “speaking“ rendition of a musical masterpiece. To acquire these specialized auditory-sensory-motor and emotional 8) ___, musicians must undergo extensive training periods over many years, which start in early childhood and continue on through stages of increasing physical and strategic complexities. Performance anxiety, linked to high societal pressures such as the fear of failure and heightened self-demands, frequently accompanies these learning processes. Motor disturbances in musicians are common and include mild forms, such as temporary motor fatigue with short-term reduction of motor skills, painful overuse injuries following prolonged practice, anxiety-related motor failures during performances (choking under pressure), as well as more persistent losses of motor control, here termed “dynamic stereotypes“ (DSs).


Musician’s dystonia (MD), which is characterized by the permanent loss of control of highly skilled movements when playing a musical instrument, is the gravest manifestation of dysfunctional motor programs, frequently linked to a genetic susceptibility to develop such motor disturbances. Motor failures in musicians develop along a continuum, starting with subtle transient degradations due to fatigue, overuse, or performance stress, which transform by and by into more permanent, still fluctuating motor degradations, the DSs, until a more irreversible condition, MD manifests.


 “Begin slowly and increase gradually any unaccustomed use of the hands.“ – Michael Charness, MD (The Musician’s Way, p. 237)


Violinist Peter Oundjian, guitarist Liona Boyd, pianists Leon Fleischer and Gary Graffman – all are musicians whose careers were upended by musicians dystonia (MD). Among the approximately 1% of musicians who develop MD, the effects are debilitating. Over time, usually decades, the program in the brain that they depend on to control their movements gets corrupted, and they lose command of certain task-specific actions. For instance, violinists with MD might experience curling of the left 3rd and 4th fingers when they play, but those fingers will function normally when they do other activities. Researchers also find that MD “appears more often in the more intensely used hand.“ Hence, violinists are more likely to be affected in the left hand, pianists in the right, although any muscle group could be involved, even arm or shoulder 9) ___. Some musicians diagnosed with MD seem to develop it without any precipitating factor aside from long-term repetitive movement. For others, the condition surfaces months or years following a change of instrument or technique, subsequent to a dramatic increase in playing time, or after they begin doing a new, skillful repetitive activity. In those types of situations, the process via which a musician’s brain acquires a new movement program corrupts the pre-existing one and then dystonic contractions result. On top of that, physician Raoul Tubiana reports that the musicians he diagnosed with MD displayed awkward postural and movement habits. It’s conceivable, then, that physical misuse contributes to provoking MD in some individuals, maybe because musicians who move awkwardly foster more convoluted and corruption-prone wiring in their brains. Given that MD can run in families, a genetic component seems certain. According to the Dystonia Medical Research Foundation, “At present, researchers have recognized multiple forms of inheritable dystonia and have identified at least 13 genes or chromosomal locations responsible for the various manifestations.“ Note that the forms of dystonia referred to in that quote don’t include MD, for which no culpable 10) ___ have yet been discovered. In light of the above information, it’s possible that some musicians could be genetically predestined to acquire MD no matter how gracefully they play owing to the way that prolonged repetitive motion affects their brains. The published research also implies that if we emphasize certain behaviors and avoid others, we can probably reduce the chances of MD arising.


Sources:; Wikipedia


A well-known scholar’s thoughtful follow-up on last week’s ON TARGET emphasis on Climate Change.


ANSWERS: 1) fingers; 2) brain; 3) maps; 4) transcranial magnetic stimulation. 5) dystonia; 6) pain; 7) neurological; 8) skills; 9) muscles; 10) genes


Leon Fleisher, Child Prodigy, Struggled to Recover from Focal Dystonia

Fleisher in 1963Photo credit: Seattle Symphony Orchestra, where he was one of their featured artists for the season; photographer: Bender – eBay itemphoto frontphoto back, Public Domain,


On July 23, 1928, Leon Fleisher was born in San Francisco into a poor Jewish family from Eastern Europe. His father’s business was hat-making, while his mother’s goal was to “make her son a great concert pianist“. Fleisher started studying the piano at age four, made his public debut at age eight, and played with the New York Philharmonic under Pierre Monteux at 16. Monteux famously called him “the pianistic find of the century.“ He became one of the few child prodigies to be accepted for study with Artur Schnabel and also studied with Maria Curcio. Fleisher was linked via Schnabel to a tradition that descended directly from Beethoven himself, handed down through Carl Czerny and Theodor Leschetizky.


“My mother was very ambitious for me and gave me a choice,“ said Fleisher. “Either I was to be the first Jewish President of the United States, or a great concert pianist. Whichever it was, I had to be perfect.“


In the 1950s, Fleisher signed an exclusive recording contract with Columbia Masterworks. He is particularly well known for his interpretations of the piano concerti of Brahms and Beethoven, which he recorded with George Szell and the Cleveland Orchestra. They also recorded Mozart’s Piano Concerto No. 25, the Grieg and Schumann piano concertos, Franck’s Symphonic Variations, and Rachmaninoff’s Rhapsody on a Theme of Paganini.


In 1964, Fleisher lost the use of his right hand, due to a condition that was eventually diagnosed as focal dystonia. At the age of 36, he could barely write his name. “I was preparing for the most important tour of my life when I had a minor accident. I cut my thumb on a piece of cheap garden furniture and required a couple of stitches. When I started practicing again, things didn’t feel quite right on my right side. My fourth and fifth fingers seemed to want to curl under. I practiced even harder, not listening to my body when, through pain, it warned me to stop. Things got progressively worse and in less than a year those two fingers were completely curved under, sticking into the palm of my hand. No way could I play the piano.“ It was as if his arm were a rope becoming unbraided, with creeping numbness in his fingers. Engagements were cancelled, recordings put on hold. “I was desolate,“ he says. “My life fell apart, and this mysterious debilitating condition destroyed my relationship with my second wife, striking deep into my family.“ Doctors were perplexed and could offer no medication or surgical repair to a condition that baffled them. Fleisher even considered suicide. “I grew a beard, wore my hair long and in a ponytail, and I got a Vespa scooter. I felt I had no purpose anymore; I was simply floundering.“


After a couple of years marking time, he realized that his connection was with music, not just with playing the piano with two hands. Out of a disastrous impediment, three new careers beckoned, the first as a left-handed concert pianist. “I thought about Paul Wittgenstein, the Austrian concert pianist whose right arm was shot off in the First World War. He commissioned works for the left hand from Richard Strauss, Korngold, Hindemith, Prokofiev, Ravel and Britten, so there was existing piano literature for pianists with no function in their right hands. And there was Brahms’ magnificent arrangement for left hand of Bach’s Chaconne for solo violin. Thank goodness it wasn’t my left hand that stopped working, since there are hardly any piano works for right hand alone. There are about 1,000 pieces for the left hand out there – most of them pretty bad – but Ravel’s Concerto for left hand, which I must have played over 1,000 times and have also conducted from the keyboard, is a masterpiece in its own right.“ “Secondly, I decided to pursue a musical career through conducting, moving from a sitting to a standing position. It felt so different to be on my feet in front of an orchestra but, worse, I immediately felt my ass to be 10 times its normal size, waving around in front of the audience.“


But it was in teaching that he found real happiness. “I became far better at explaining those elusive areas of expression and nuance that are so difficult to express in words.“ Indeed, his masterclasses, in which, as tutor, it is irrelevant whether you can use five or 10 fingers, are models of gently humorous correction and deeply-felt inspiration. He never gave up the idea of returning to two-handed repertoire. After leaving the concert platform in 1965, Fleisher tried every kind of medical, psychiatric and alternative treatment, from acupuncture and hypnosis to deep-tissue massage, Tiger Balm and others, including more than a few drams of Scotch. But, as a result of conducting and grasping the baton too tightly, he developed carpal tunnel syndrome. This weakness in the forearm and hand caused by pressure on a nerve in the wrist could be alleviated only through surgery. Fleisher agreed to have his wrist cut open with a knife, to the accompaniment, he remembers, of a recording of Mahler’s First Symphony. Astonishingly, the surgery for one ailment helped the other, and his fingers began to straighten out. “After 18 years, I was able to play again. In 1982, I was invited to open the new Meyerhoff concert hall in Baltimore and made the front page of The New York Times for being able to use both hands for the first time since 1965.“ But this supposed cure proved short-lived. “I knew things weren’t quite as they should be,“ said Fleisher. “I had to change the advertised program from Beethoven’s Fourth Piano Concerto to Franck’s Symphonic Variations. It didn’t feel to me like a triumphant return. I broke down in tears in the dressing-room before the concert and felt awful at having to go through an evening of pretense.“


For the remaining 12 of that series of “comeback“ concerts, Fleisher reverted to left-hand repertoire. Only in 1995 was he finally diagnosed with a neurological disorder called focal dystonia. “It’s a malady caused by the brain learning to do a wrong thing, and though a cure has been found, I am a dystonic for life. It’s task-specific. Glass-blowers get it, computer workers can become afflicted and golfers begin to miss their putts.“ Fleisher thinks there could be 10,000 musicians around the world suffering from the condition and that the composer-pianist Robert Schumann may have been an early victim, causing permanent damage by mechanically exercising his troublesome fourth finger.


Fifteen years ago, Botox was still in its experimental stages. However, a small dose injected directly into the appropriate muscle along with holistic massage therapy involving connective tissues restored Fleisher’s fingers sufficiently for him to return to two-handed performances. A tiny amount of Botox relaxes the fingers without causing the paralysis, evident when it is used to reduce facial wrinkles by immobilizing muscles. Crucially, there is no sign of any of the negative effects, such as a diminished quality of emotional experience. In 1995, Fleisher made a second comeback, quietly and without any hype, as he tested his stamina. Only after proving himself to himself did he feel ready to resume his career as a two-handed solo pianist. In 2005, he gave 40 concerts in 31 cities and the following year enjoyed success at New York’s Carnegie Hall. The same two fingers on Fleisher’s right hand still want to curl, but Botox injections every four months keep the condition under control.


When asked if he dances, Fleisher roars with laughter. “Wouldn’t that be a lovely idea?“ he exclaims. “I’m afraid my feet follow my hands. In fact, I have two left feet! It’s a deep regret, along with the fact that I am totally ungifted when it comes to jazz.“ According to his singer-songwriter son Julian, though, Fleisher does have something in common with great jazz players: the importance he places on rhythm. Fleisher feels rhythm as the heartbeat of music. “It regulates the metabolism of the piece, motivates the music and, if it’s infectious enough, makes us tap our toes.“


In 2004, Vanguard Classics released Leon Fleisher’s first “two-handed“ recording since the 1960s, entitled “Two Hands“, to critical acclaim. Two Hands is also the title of a short documentary on Fleisher by Nathaniel Kahn which was nominated for an Academy Award for best short subject on January 23, 2007. Fleisher received the 2007 Kennedy Center Honors. Kennedy Center Chairman Stephen A. Schwarzman described him as “a consummate musician whose career is a moving testament to the life-affirming power of art.“ Fleisher’s musical interests extend beyond the central German Classic-Romantic repertory. The American composer William Bolcom composed his Concerto for Two Pianos, Left Hand for Fleisher and his close friend Gary Graffman, who has also suffered from debilitating problems with his right hand. It received its first performance in Baltimore in April 1996. The concerto is so constructed that it can be performed in one of three ways, with either piano part alone with reduced orchestra, or with both piano parts and the two reduced orchestras combined into a full orchestra.


In 2004, Leon Fleisher played the world premiere of Paul Hindemith’s Klaviermusik (Piano Concerto for the Left Hand), Op. 29, with the Berlin Philharmonic. This work was written in 1923, for Paul Wittgenstein, who disliked and refused to play it. However, he had sole performing rights and kept the score, not allowing any other pianists to play it. The manuscript was discovered among his papers after the death of his widow in 2002. On October 2, 2005, Fleisher played the American premiere of the work, with the San Francisco Symphony under Herbert Blomstedt. In 2012, at the invitation of Justice Ruth Bader Ginsburg, Fleisher performed at the Supreme Court of the United States. Fleisher has continued to be involved in music, both conducting and teaching at the Peabody Conservatory of Music, the Curtis Institute of Music, and the Royal Conservatory of Music in Toronto; he is also closely associated with the Tanglewood Music Center. With Dina Koston, he co-founded and co-directed the Theater Chamber Players in 1968-2003, which was the first resident chamber ensemble of the Smithsonian Institution and of The Kennedy Center. Among others, Fleisher has taught Jonathan Biss, Yefim Bronfman, Phillip Bush, Naida Cole, Jane Coop, Enrico Elisi, Enrique Graf, Helene Grimaud, Hao Huang, Kevin Kenner, Dina Koston, Louis Lortie, Wonny Song, Andre Watts, Jack Winerock, Daniel Wnukowski, Alon Goldstein, Dale Anthony and Orit Wolf.


His memoir, My Nine Lives, co-written with the Washington Post music critic Anne Midgette, appeared in November 2010.


Three-In-One Antibody Protects Monkeys From HIV-Like Virus


According to an article published in Science (20 September 2017), a three-pronged antibody made in the laboratory protected monkeys from infection with two strains of SHIV, a monkey form of HIV, better than individual natural antibodies from which the engineered antibody is derived. The three-pronged antibody was created by investigators from the National Institutes of Health (NIH) and the Paris-based pharmaceutical company Sanofi, also stopped a greater number of HIV strains from infecting cells in the laboratory more potently than natural, single antibodies. This new broadly neutralizing antibody binds to three different critical sites on HIV. According to the NIH, combinations of antibodies that each bind to a distinct site on HIV may best overcome the defenses of the virus in the effort to achieve effective antibody-based treatment and prevention, and that the concept of having a single antibody that binds to three unique sites on HIV is certainly an intriguing approach.


For the study, the authors tested dozens of bispecific and trispecific antibodies in the laboratory to find the best-performing combination. Individual antibodies were combined into trispecific antibodies using technology proprietary to Sanofi. The most successful formula combines the unique structures of the broadly neutralizing HIV antibodies called VRC01, PGDM1400, and 10E8v4. The authors then tested this trispecific antibody in an experiment involving monkeys and two strains of SHIV. One SHIV strain is sensitive to neutralization by VRC01 and the trispecific antibody, but resistant to neutralization by PGDM1400. The other SHIV strain is sensitive to neutralization by PGDM1400 and the trispecific antibody, but resistant to neutralization by VRC01. Twenty four monkeys were treated: 8 with VRC01, 8 with PGDM1400, and 8 with the trispecific antibody. Five days later, the all of the 24 monkeys were exposed to both SHIV strains. Results showed that 5/8 of the monkeys that received PGDM1400 and 6/8 of the monkeys that received VRC01 became infected with SHIV, but 0/8 of the monkeys that received the trispecific antibody became infected.


Sanofi is manufacturing the trispecific antibody for use in a Phase 1 clinical trial that will be conducted by NIAID to test the antibody’s safety and pharmacokinetics in healthy people beginning in late 2018. Discussions also are under way with the NIAID-funded AIDS Clinical Trials Group to conduct a separate Phase 1 clinical trial of the antibody in people living with HIV. By binding to three different sites on the virus, the new antibody should be harder for HIV to dodge than natural, single antibodies.


According to the authors, the ability of trispecific antibodies to bind to three independent targets at once could make them a useful prototype for treatments developed not only for HIV but also for other infectious diseases, autoimmune diseases and cancers.



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Successful Treatment of Lethal Brain Cancers in Mice


High-grade gliomas cause more deaths than any other form of brain cancer, partly due to the extreme difficulty surgeons have in removing all of the tumor cells. This leaves clinicians dependent on traditional chemotherapy and radiation treatments that have limited success. Depending on the specific subtype of tumor, more than three-quarters of patients die within five years, and for the most common childhood glioma that number exceeds 99%.


According to an article published in Nature (20 September 2017), a study conducted in mice provides evidence that highly lethal brain tumors, called high-grade gliomas, stop growing when deprived of a specific molecule naturally produced when brain cells fire. The study suggest that targeting a protein called neuroligin-3 may prove beneficial in patients with these diseases. According to the NIH, this study transforms our understanding of how neurons influence the growth of gliomas, and opens a new door for potential treatments.


In a 2015 paper published in Cell, the research team identified several chemicals released by brain cells in response to neural activity that cause high-grade gliomas to grow. One of them was neuroligin-3, a protein that helps neurons communicate. In the current study, the authors extracted tumor cells from patients with several varieties of high-grade gliomas and inserted them into the brains of two breeds of mice, one normal and one lacking the gene that produces neuroligin-3. In the latter, none of the tumors grew substantially for four and a half months and roughly half remained stagnant after six months, whereas tumors grew markedly in the mice with an intact neuroligin-3 gene. Further experiments suggested neuroligin-3 triggers a series of chemical reactions that stimulates multiple signaling pathways involved in glioma growth, causing the tumors to expand.


The team also discovered that neuroligin-3 release is triggered when active neurons secrete a protein called ADAM10, which causes neuroligin-3 to detach from the surface of cells. Stopping neurons from firing prevented the release of both ADAM10 and neuroligin-3, and genetically deleting ADAM10 from neurons in mice reduced neuroligin-3 release. In addition, the team found that a group of brain cells called oligodendrocyte precursor cells can release neuroligin-3, suggesting those cells may play a role in accelerating glioma growth. Finally, the authors showed that blocking ADAM10 activity with a drug designed to treat other types of cancers dramatically reduced the growth of two types of gliomas implanted into the brains of mice.


In addition to working towards a better understanding of why gliomas are so dependent on neuroligin-3 for growth, the authors are planning to initiate a clinical trial using an ADAM10 inhibitor in human glioma patients. Although treatments targeting ADAM10 and neuroligin-3 might extend patients’ lifespans, they would not kill the tumors, making additional treatments necessary to cure the disease.


Making Advances Against Sickle Cell Disease


The following was abstracted from FDA Voice posted on September 26, 2017


The medical definition of sickle cell disease – a group of inherited red blood cell disorders caused by abnormal hemoglobin, called hemoglobin S or sickle hemoglobin, in red blood cells – does not come close to describing the condition from the patient’s perspective. Sickle cell disorders have devastating effects on patients and their families. Patients often experience recurrent episodes of excruciating pain, or sickle cell crisis, debilitating fatigue, infections, cognitive disorders, strokes, a life-threatening condition called acute chest syndrome, and damage to their vital organs, tissues, and bones. In some patients, the disease may trigger frequent and very painful sickle cell crises that require hospitalization. In others, it may cause less frequent and milder attacks. Although mortality during childhood has improved progressively, the life expectancy among individuals with sickle cell disease in the United States is on average 30 years less than the general population.


Sickle cell is a rare disease. According to the Centers for Disease Control and Prevention, about 1 of every 365 African-Americans and about 1 out of every 16,300 Hispanic-Americans are born with sickle cell disease. In addition, more than 2 million people carry the sickle cell gene that enables them to possibly pass the disease on to their children. Today, bone marrow transplantation offers the only potential cure for this disorder; but finding a donor is difficult and the procedure has serious risk.


As Sickle Cell Awareness Month comes to a close this September, FDA reports on how much must be done to help patients in need and educate others on sickle cell disease – and also to recognize progress and hope for a better future.


In July, FDA approved Endari (L-glutamine oral powder) to reduce the severe complications from the blood disorder in patients age 5 years and older. Endari is only the second FDA-approved treatment for this disorder and the first since hydroxyurea was approved nearly 20 years ago. Studies showed that patients taking Endari experienced fewer trips to the emergency room and fewer hospitalizations for sickle cell pain than those given a placebo. They also had fewer occurrences of acute chest syndrome. Common side effects include constipation, nausea, headache, abdominal pain, cough, pain in the extremities, back pain, and chest pain.


FDA continues to work with all interested parties in improving the lives of patients with sickle cell disease. In February 2014, FDA held the first ever federal meeting with patients as part of our Patient Focused Drug Development program. A highlight was learning what symptoms bothered patients the most in their daily lives – the sort of information that can help inform the development and use of patient reported outcomes. And for the past several years, FDA clinical review staff has organized meetings to facilitate drug development in sickle cell disease. During these events, academic researchers, clinicians and FDA have engaged in an interactive discussion on trial design, potential endpoints, and patient reported outcomes.


Sickle cell disease describes a group of inherited red blood cell disorders caused by abnormal hemoglobin, the protein that carries oxygen throughout the body. Normal hemoglobin moves easily through blood vessels, but sickle hemoglobin can be crescent or sickle shaped, which causes it to stick on vessel walls, blocking or stopping the flow of blood. (Source, FDA Blog)


It is not entirely clear why progress in developing treatments for sickle cell disease has been slow. One challenge has been the multi-faceted nature of sickle cell disease as well as difficulty in defining biochemical endpoints and targets of clinical benefit in clinical trials. But there is hope. Since 2010, FDA has seen a rise in the number of industry meetings, clinical trial development and investigational new drug (IND) submissions for sickle cell disease (required when companies want to conduct clinical trials of an investigational new drug), which may qualify for an expedited approval program known as Fast Track. Patient-reported outcome measures are being incorporated into clinical trials for new products. Currently 143 clinical trials (on are recruiting patients studying drug interventions, gene therapy, behavioral treatment and diagnostic testing in both adults and children.


While the Center for Drug Evaluation and Research (CDER) work to encourage drug development, other efforts are underway to make bone marrow transplantation accessible to more patients as well as utilizing gene editing which can provide a permanent cure for sickle cell disease by correcting the sickle mutation in the stem cells. FDA knows there is much more work to be done, but FDA says it is proud to say during this Sickle Cell Awareness Month, that we are part of a dynamic team and remain committed to promoting the development of safe and effective treatments for this blood disorder.


For more information, please visit: The FDA Encourages New Treatments for Sickle Cell Disease


Roast Cardamom/Curry Chicken Thighs with Sumac, Cilantro, Mango, Dates and Chopped Pistachios

There are three aspects of my latest recipe that make it especially good: First, you marinate ingredients overnight. Second: the wide variety of herbs and spices, creates the depth and levels of flavor. Third: the 25 fresh garlic cloves, surprise many people; however, if roasted long enough, garlic takes on an unbelievably sweet nutty taste, without which this recipe would not be as good as it is. Put off making this, until you have collected all the spices. I get my spices from, FreshDirect and a little family owned Asian market a few blocks away. Once you have all the herbs and spices, give it a try. It’s worth it! The second time I experimented with this recipe, was to show off with our wonderful house guests, who, I might add, gobbled it up, with nothing left over. Because the natural juices are so-o flavorful, you’ve got to serve this chicken dish with rice, couscous, mashed potatoes, risotto, or orzo, to help soak up the gravy au natural. In addition, serve warm pita or flat bread to sop up the juices. ©Joyce Hays, Target Health Inc.



Zest of 1 fresh lemon

4 Tablespoons freshly squeezed lemon juice

1 teaspoon kosher salt

Zest of 1 fresh orange

4 Tablespoons freshly squeezed orange juice

Zest of 1 fresh lime

4 Tablespoons freshly squeezed lime juice

5 Tablespoons extra virgin olive oil

1 teaspoon sumac

2 Tablespoons whole grain mustard

4 Tablespoons honey

1/2 cup cream sherry or Madeira

1/2 cup chicken stock or broth

1 bay leaf

1 pinch chili flakes

1 pinch black pepper

1 teaspoon turmeric

1 teaspoon cumin

1 teaspoon cardamom

2 teaspoons curry powder

8 chicken thighs (skin on, bone in)

3 cups sliced carrots (1/4-inch thick)

1 onion, halved and thinly sliced

25 fresh garlic cloves, sliced

2 cups sliced dates

3 mangos cut in cubes

1 Tablespoon fresh thyme leaves

2/3 cup fresh cilantro, well chopped

2/3 cup fresh parsley, well chopped

2 scallions, chopped (for roast)

2 scallions, thinly sliced (for garnish)

1/2 cup pistachio nuts, toasted, then chopped, for garnish


This recipe is great because of the myriad of ingredients like orange, lemon, lime, mango and dates. I’m also experimenting with new spices like sumac. The Madeira also adds a special touch. In my recipe for chopped chicken liver, I swear it’s the Madeira that makes such a difference. ©Joyce Hays, Target Health Inc.



1. Do all of your chopping, slicing, zesting, first.

Chop several items on one cutting board, to save time. Here, we’re slicing onion, garlic and carrots. ©Joyce Hays, Target Health Inc.


Having peeled 3 mangos, we’re now cutting into bitesize pieces. ©Joyce Hays, Target Health Inc.


2. Zest of one lemon

3. Zest of one orange

4. Zest of one lime

5. Quarter the lemon, lime and the orange lengthwise, removing any seeds. Thinly slice crosswise into small wedges Reserve slices.

6. In a saucepan, whisk together lemon juice, lime juice, orange juice, oil, mustard, honey, salt, bay leaf, chili flakes and black pepper. Bring to a boil and simmer for 5 minutes. Let cool.


Mustard-honey mixture is now cooling. ©Joyce Hays, Target Health Inc.


7. In a very large bowl, add the honey mixture. Next, add carrots, onion, garlic slices, chopped scallions, dates, thyme, curry, flax seeds, cream sherry, chicken stock or broth, orange and lemon slices, cilantro. Stir this mixture several times.

8. Add chicken thighs to the bowl with sauce, stir sauce over the chicken several times. Cover and let marinate overnight in the refrigerator.


All of the ingredients will be covered and marinate overnight in the fridge. Joyce Hays, Target Health Inc.


9. Heat oven to 425 degrees.

10. Line a large roasting dish with parchment (optional) to make cleaning easier, later.

11. Transfer all ingredients, including all of the marinade, to a large roasting dish that can go from oven to table. Chicken should be skin side up.


This is my favorite oven to table large size, baking dish. –  From your bowl of marinating ingredients, first put the chicken into the baking dish, with the skin side facing up. Then slowly, with a large spoon, add all of the fruit and veggies, over the chicken. Finally, add all of the liquid. ©Joyce Hays, Target Health Inc.


Going into oven to roast. Another secret of this flavorful recipe, is the amount of fresh sliced garlic. When I told our house guests that there were 25 garlic cloves (large slices), they were quite surprised. People don’t realize that when you roast garlic for this amount of time, it becomes sweet and so delicious, you can eat it plain, as a regular vegetable. ©Joyce Hays, Target Health Inc.


Out of the oven. This chicken is so moist and delicious! I must confess that as I’m putting this newsletter together, everything about this recipe is making me hungry. ©Joyce Hays, Target Health Inc.


12. Roast until chicken is browned and cooked through, about 30 to 40 for thighs.

13. While chicken is roasting, make saffron jasmine rice, with curry, golden raisins, and toasted pine nuts

14. When the chicken is done, give the sauce in the pan a stir; if the sauce looks too dry add 2 to 3 Tablespoons chicken stock or broth or wine. Add the parsley and scallions and stir into the sauce. If you want the sauce thicker, mix some chickpea flour into several Tablespoons of plain Greek yogurt, and add to the sauce, mixing the flour very well into the rest of the sauce.

15. Continue roasting the carrots until they are tender, about 7 to 12 minutes longer.

16. Serve the chicken and saffron rice with sauce spooned over.

17. Sprinkle the chicken with the toasted, chopped pistachio nuts.


The aroma of herbs and spices filled the air and beckoned us to begin the feast, which we did with gusto! ©Joyce Hays, Target Health Inc.


With our relatives visiting us from Germany, we started this meal with chilled Pouilly-Fuisse and a tomato/avocado/cucumber salad with an extra virgin olive oil & fresh lemon, dressing. Then the new recipe, the chicken thighs with all of the luscious gravy, served over one of my oldest most reliable recipes, saffron/curry rice with golden raisins and toasted pine nuts. Both dishes will be finished by the time we clear the table for dessert; which is a simple and refreshing, strawberry/blueberry mousse. ©Joyce Hays, Target Health Inc.


Dessert: Fresh mango, Cheese & grapes, Blueberry cake. ©Joyce Hays, Target Health Inc.


Last week, we all saw Mary Jane by playwright, Amy Herzog at New York Theater Workshop, where THI is a patron. On another evening, we saw Prince of Broadway, a lovely musical review of some of the productions of director/producer, Hal Prince. Prince of Broadway was playing at the Samuel J. Friedman, Broadway Theater of Manhattan Theater Club, where THI is also a patron. We enjoyed both of these shows and recommend them highly.


From Our Table to Yours

Bon Appetit!