NIH Collaboratory Webinar: John Laschinger, MD and Jules Mitchel, PhD to Present the CTTI Registry Trial Project

 

Target Health has been a member of the Clinical Trials Transformation Initiative (CTTI) since 2008, and we strongly support CTTI’s mission of transforming and modernizing clinical trials. While it has been a long journey, there have been many fruits of our labors, including the Registry Work Stream, which culminated in a CTTI Webinar in May, and now an NIH Collaboratory Webinar being held this month.

 

Here are the Collaboratory details:

 

On Friday, July 21, 2017, 1:00-2:00 p.m. EDT, John Laschinger, MD, Medical Officer, Center for Devices and Radiological Health, Clinical Trials Operations and Biostatistics Branch, US FDA, and Jules Mitchel, MBA, PhD, President, Target Health Inc. will be presenting the “CTTI Registry Trials Project: Evaluation and Design of Registries for Conducting Clinical Trials.“ For more information go to https://www.nihcollaboratory.org/Lists/Calendar/DispForm.aspx?ID=253.

 

This webinar covers CTTI’s recommendations on conducting clinical trials using registries. Those interested in evaluating or designing a registry for the purposes of conducting clinical trials can learn more about the project’s tools, intended for the following purposes:

 

1. To determine if an existing registry is appropriate for embedding clinical trials

2. To assess if an existing registry contains the elements needed to support a clinical trial

3. To design a new registry suitable for embedding clinical trials

 

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, and if you like the weekly newsletter, ON TARGET, you’ll love the Blog.

 

Joyce Hays, Founder and Editor in Chief of On Target

Jules Mitchel, Editor

 

QUIZ

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Chrondrodermatitis Nodularis Helicas (CNH)

Chondrodermatitis helicis nodularis in a 67-year-old man. Photo credit: Klaus D. Peter, Gummersbach, Germany – Own work (own photograph), CC BY 3.0 de; Wikipedia Commons

 

The word dermatology derives from the 1) ___ dermatos and derma, meaning “skin.“ Originally it meant “to flay“ skin.

 

Chondrodermatitis nodularis chronica helicis (CNH), also known as chondrodermatitis nodularis helicis, is a small, nodular, tender, chronic inflammatory lesion occurring on the helix of the 2) ___. CNH is a common, benign, painful condition of the helix or antihelix of the ear which more often affects middle-aged or older men, but cases are also reported in women. In a 2006 report by Rex et al., of 74 patients treated for CNH, 72.9% of patients were 3) ___ while 16.2% were women.

 

Pediatric cases of CNH have also been reported, with one case reported in a 9-month-old infant. This case indicated that the infant slept on the ear of occurrence, where she developed 2 nodules. The infant had also recently started sleeping on a hard pillow, which may have contributed to the lesion. An excisional biopsy of the lesion at 9 months showed histologic features consistent with CNH. The papule resolved with a change in sleeping 4) ___ over 6 months.

 

The exact cause of CNH is unknown, although most experts believe it is caused by prolonged and excessive pressure. Several anatomic features of the ear predispose persons to the development of this condition. The ear has relatively little subcutaneous tissue for insulation and padding, and only small dermal blood 5) ___ supply the epidermis, dermis, perichondrium, and cartilage. Dermal inflammation, edema, and necrosis from trauma, cold, actinic damage, or pressure probably initiate the disease. In most cases, focal pressure on the stiff cartilage most likely produces damage to the cartilage and overlying skin. Anatomic features of the ear, as listed above, prevent adequate healing and lead to secondary perichondritis. The 6) ___ ear is more commonly involved. A 2009 report concluded that specific perichondrial arteriolar changes may be the cause of CNH. Although physicians have regarded CNH as an idiopathic disorder with no systemic associations, exceptions to this have been noted. CNH may also occasionally be associated with autoimmune or connective-tissue disorders, including autoimmune thyroiditis, lupus erythematosus, dermatomyositis, and scleroderma. Such cases may be more common in pediatric or young adult female patients. A 2009 report detailed CNH in monozygotic twins, suggesting a possible 7) ___ factor. The exact incidence of CNH is unknown. While the incidence in patients age 60-80 years is predominantly male, cases presenting in young 8) ___ appear to be associated with evidence of underlying systemic illness in some instances. CNH has been reported to occur most commonly in fair-skinned individuals with severely 9) ___-damaged skin; however, it can occur in persons of any races. The prognosis for patients with CNH is 10) ___, although long-term morbidity is common. Spontaneous resolution is the exception; remissions may occur, but CNH usually continues unless adequately treated.

 

ANSWERS: 1) Greek; 2) ear; 3) men; 4) position; 5) vessels; 6) right; 7) hereditary; 8) females; 9) sun; 10) excellent

 

Peter Wisch MD and his very sympatico nurse, Agata Tuszakowski, photo taken today at the end of my appointment. I thought I had a cancerous growth but the quick diagnosis was: Chondrodermatitis Nodularis Helicas. Dr. Wisch is the best dermatologist in New York, and has been our family’s dermatologist, for many years. His manner is kind, informative, reassuring and relaxing. We recommend Dr. Wisch highly for anyone looking for an excellent physician.

Moritz Kaposi, MD

Moritz Kaposi – Photo credit: Unknown – Images from the History of Medicine (NLM), Public Domain; Wikipedia Commons

 

According to his biographer, Dr. J.D. Oriel, “in his lifetime, Moritz Kaposi, MD, was acknowledged as one of the great masters of the Vienna School of Dermatology, a superb clinician and renowned teacher“. While his mentor, Ferdinand von Hebra, is considered the “father of dermatology“, Kaposi was one of the first to establish dermatology on its anatomical pathology scientific basis. He became the chairman of the Vienna School of Dermatology, after Hebra’s death in 1880.

 

Moritz Kaposi, a Hungarian physician, was born on 23 October 1837 in Kaposvar, Austria-Hungary and died on 6 March 1902 in Vienna. This well-known physician is best known as the dermatologist who discovered the skin tumor that received his name (Kaposi’s sarcoma). Kaposi was born to a Jewish family, whose original surname was Kohn. But with his conversion to the Catholic faith, he changed it to Kaposi in 1871, in reference to his town of birth. One purported reason behind this is that he wanted to marry a daughter of current dermatology chairman, Ferdinand Ritter von Hebra, and advance in the society, which he could not have done being of Jewish faith. This seems unlikely because he married Martha Hebra and converted to Catholicism several years prior to changing his name, by which time he was already well established in the Vienna University faculty and a close associate of von Hebra. A more plausible explanation is based on his own comments to colleagues that he changed his name to avoid confusion with five other similarly named physicians on the Vienna faculty. Rumors about the sincerity of both his marriage and his concerns about his Jewish ancestry may have arisen through professional jealousy. According to William Dubreuilh (1857-1935), first professor and chairman of dermatology in Bordeaux: “On disait de Kaposi qu’il avait pris la fille de Hebra, sa maison, sa chaire et sa clientele, laissant le reste a son beau-frere Hans Hebra.“ – “It was said of Kaposi that he had taken the daughter of Hebra, his home, his chair and his clientele, leaving the rest to his brother-in-law, Hans Hebra.“

 

In 1855, Kaposi began to study medicine at the University of Vienna and attained a doctorate in 1861. In his dissertation, titled Dermatologie und Syphilis (1866), he made an important contribution to the field. Kaposi was appointed as professor at the University of Vienna in 1875, and in 1881 he became a member of the board of the Vienna General Hospital and director of its clinic of skin diseases. Together with his mentor, Ferdinand Ritter von Hebra, he authored the book Lehrbuch der Hautkrankheiten (Textbook of Skin Diseases) in 1878. Kaposi’s main work, however, was Pathologie und Therapie der Hautkrankheiten in Vorlesungen fur praktische Arzte und Studierende (Pathology and Therapy of the Skin Diseases in Lectures for Practical Physicians and Students), published in 1880, which became one of the most significant books in the history of dermatology, being translated to several languages. Kaposi is credited with the description of xeroderma pigmentosum, a rare genetic disorder now known to be caused by defects in nucleotide excision repair (“Ueber Xeroderma pigmentosum. Medizinische Jahrbucher, Wien, 1882: 619-633“). Among other diseases, Kaposi was the first to study Lichen scrofolosorum and Lupus erythematosus. In all, he published over 150 books and papers and is widely credited with advancing the use of pathologic examination in the diagnosis of dermatologic diseases.

 

Kaposi’s name entered into the history of medicine in 1872, when he described for the first time Kaposi’s sarcoma, a cancer of the skin, which he had discovered in five elderly male patients and which he initially named “idiopathic multiple pigmented sarcoma“. More than a century later, the appearance of this disease in young gay men in New York City, San Francisco and other coastal cities in the United States was one of the first indications that a new disease, now called AIDS, had appeared. In 1993, the discovery that Kaposi’s sarcoma was associated with the herpesvirus, sparked considerable controversy and scientific in-fighting until sufficient data had been collected to show that indeed KSHV was the causative agent of Kaposi’s sarcoma. The virus is now known to be a widespread infection of people living in sub-Saharan Africa; intermediate levels of infection occur in Mediterranean populations (including Israel, Saudi Arabia, Italy and Greece) and low levels of infection occur in most Northern European and North American populations. Kaposi’s sarcoma is now the most commonly reported cancer in parts of sub-Saharan Africa. Kaposi’s sarcoma is usually a localized tumor that can be treated either surgically or through local irradiation. Chemotherapy with drugs such as liposomal anthracyclines or paclitaxel may be used, particularly for invasive disease. Antiviral drugs, such as ganciclovir, that target the replication of herpesviruses such as KSHV have been used to successfully prevent development of Kaposi’s sarcoma, although once the tumor develops these drugs are of little or no use.

 

Single-Gene Mutations Lead to Atopic Dermatitis

 

According to an article published online in Nature Genetics (2 July 2017), mutations have been identified in a gene called CARD11 that lead to atopic dermatitis, or eczema, an allergic skin disease. The mutations were discovered in four unrelated families with severe atopic dermatitis, with subsequent identification of cell-signaling defects that contribute to allergic disease. Their findings also suggest that some of these defects potentially could be corrected by supplementation with the amino acid glutamine.

 

For the study, the authors analyzed the genetic sequences of patients with severe atopic dermatitis and identified eight individuals from four families with mutations in the CARD11 gene, which provides instructions for production of a cell-signaling protein of the same name. While some people with these mutations had other health issues, such as infections, others did not, implying that mutations in CARD11 could cause atopic dermatitis without leading to other medical issues often found in severe immune system syndromes. The authors next set out to understand how the newly discovered CARD11 mutations contribute to atopic dermatitis. Each of the four families had a distinct mutation that affected a different region of the CARD11 protein, but all the mutations had similar effects on T-cell signaling. With cell culture and other laboratory experiments, the authors determined that the mutations led to defective activation of two cell-signaling pathways, one of which typically is activated in part by glutamine. Then, growing cultured T cells from patients with CARD11 mutations with excess glutamine, boosted mTORC1 activation, a key part of one of the affected pathways. This suggested that the potential to partially correct the cell-signaling defects that may contribute to atopic dermatitis. The authors are now planning a study to assess the effect of supplemental glutamine and leucine, another amino acid that activates mTORC1, in people with atopic dermatitis with and without CARD11 mutations.

 

Eye Microbiome Trains Immune Cells to Fend Off Pathogens

 

For years, the ocular surface was thought to be sterile because of the presence of an enzyme called lysozyme that destroys bacteria, antimicrobial peptides, and other factors that rid the eye of microbes that may land from the air (or from our fingers) onto the surface of the eye.

 

According to an article published in the journal Immunity (27 June 2017), a study has demonstrated the existence of a resident ocular microbiome that trains the developing immune system to fend off pathogens. And yes there is a resident microbe living on the surface of the eye that protects the cornea from infection. According to the authors, this is the first evidence that a bacterium can live for a long time on the ocular surface, and that this study addresses a longstanding question about whether there is a resident ocular microbiome.

 

For the study, the authors were able to culture bacteria from the mouse conjunctiva, the membrane that lines the eyelids, and they found several species of Staphylococci, which are commonly found on the skin, and Corynebacterium mastitidis (C. mast). However, it wasn’t clear whether those microbes had just arrived on the eye and were en route to being destroyed, or whether they lived on the eye for extended periods of time. During the study, the authors found that C. mast, when cultured with immune cells from the conjunctiva, induced the production of interleukin (IL)-17, a signaling protein critical for host defense. Upon further investigation, they found that IL-17 was produced by gamma delta T cells, a type of immune cell found in mucosal tissues. IL-17 attracted other immune cells called neutrophils — the most abundant type of white blood cell — to the conjunctiva and induced the release of anti-microbial proteins into the tears. The authors are currently investigating the unique features that can make C. mast resistant to the immune response that it itself provokes and allow it to persist in the eye.

 

To determine whether the microbe was contributing to the immune response in mice, the authors formed two groups, one control (with C. mast) and one treated with an antibiotic to kill C. mast and other ocular bacteria, and then challenged them with the fungus, Candida albicans. The mice receiving antibiotics had a reduced immune response in their conjunctiva and were not able to eliminate C. albicans, leading to full-blown ocular infection. The control mice with normal C. mast on the other hand were able to fend off the fungus. The authors also noticed that mice from the NIH animal facility had C. mast on their eyes, but mice from the Jackson Laboratory (JAX) in Maine and other commercial vendors did not. This fortuitous observation allowed the authors to determine if C. mast was truly a resident microbe, as opposed to a transient microbe that lands on the eye from the environment. They did this by inoculating C. mast-free mice with the microbe and determining if the microbe could be cultured from those animals’ eyes many weeks later. They also determined whether the microbe could easily be transmitted among cagemates. When inoculated with C. mast, JAX mice produced conjunctival gamma delta T cells that released IL-17. Bacteria could still be cultured from their eyes after many weeks. By contrast, several other strains of bacteria inoculated onto the eyes of JAX mice disappeared without inducing local immunity. Interestingly, C. mast was not spread to cage-mates even after eight weeks of co-housing; however, C. mast can be passed from mother to pup. Both of these observations support the notion that C. mast is a resident commensal, not a bacterium that is continually re-introduced to the eye from the skin or the environment.

 

According to the authors, although C. mast appears to stimulate a beneficial immune response, there may be situations in which it could cause disease. For example, the elderly tend to have suppressed immune systems, which might allow C. mast to grow out of control and cause disease. The authors are currently investigating whether other bacteria play a role in regulating eye immunity.

 

FDA Unveils Plan to Eliminate Orphan Designation Backlog

 

For our last Orphan Drug Designation Request, FDA told us that there could be a 6 month review time. We did contact the Division and were told about the major backlog.

 

As authorized under the Orphan Drug Act, the Orphan Drug Designation Program provides orphan status to drugs and biologics that are defined as those intended for the safe and effective treatment, diagnosis or prevention of rare diseases, which are generally defined as diseases that affect fewer than 200,000 people in the United States. Orphan designation qualifies the sponsor of the drug for various development incentives, including tax credits for clinical trial costs, relief from prescription drug user fee if the indication is for a rare disease or condition, and eligibility for seven years of marketing exclusivity upon approval. A request for orphan designation is one step that can be taken in the drug development process and is different than the filing of a marketing application with the FDA.

 

The FDA has unveiled a strategic plan to eliminate the existing orphan designation request backlog and ensure continued timely response to all new requests for designation with firm deadlines. The agency’s Orphan Drug Modernization Plan comes a week after FDA Commissioner Scott Gottlieb committed to eliminating the backlog within 90 days and responding to all new requests for designation within 90 days of receipt during his testimony before a Senate subcommittee.

 

Currently, the FDA has about 200 orphan drug designation requests that are pending review. The number of orphan drug designation requests has steadily increased over the past five years. In 2016, the FDA’s Office of Orphan Products Development received 568 new requests for designation – more than double the number of requests received in 2012. The increased interest in the program is a positive development for those with rare diseases and under this new plan, the agency remains committed to advancing the program to ensure it can efficiently and adequately review these requests.

 

This is the first element of several efforts the FDA will undertake under its new “Medical Innovation Development Plan,“ which is aimed at ensuring that the FDA’s regulatory tools and policies are modern, risk based, and efficient. The goal of the plan is to seek ways the FDA can help facilitate the development of safe, effective and transformative medical innovations that have the potential to significantly impact disease and reduce overall health care costs. Among the elements of the plan to eliminate the backlog, the FDA will deploy a Backlog SWAT team comprised of senior, experienced reviewers with significant expertise in orphan drug designation. The team will focus solely on the backlogged applications, starting with the oldest requests. The agency will also employ a new streamlined Designation Review Template to increase consistency and efficiency of its reviews. The program will also look to collaborate within the agency’s medical product centers to create greater efficiency, including conducting joint reviews with the Office of Pediatric Therapeutics to review rare pediatric disease designation requests.

 

To ensure all future requests receive a response within 90 days of receipt, the agency will take a multifaceted approach. These efforts include, among other new steps: reorganizing the review staff to maximize expertise and improve workload efficiencies; better leveraging the expertise across the FDA’s medical product centers; and establishing a new FDA Orphan Products Council that will help address scientific and regulatory issues to ensure the agency is applying a consistent approach to regulating orphan drug products and reviewing designation requests.

 

The FDA intends to communicate around the successful elimination of the backlog by mid-September and will soon provide more information about the Medical Innovation Development Plan.

 

Red Cabbage Salad with Goat Cheese, Cilantro, Dates, Flax and Black Sesame Seeds

On one hot evening, last week, this is what we had for dinner: veggie burgers, this red cabbage salad recipe that has been perfected over the years, and sweet ripe fresh mango slices. This was the perfect summer meal, so we wanted to share it with you.

 

Ingredients

1.5 pounds (more or less) red cabbage, sliced very thin on a mandolin

2 heaping Tablespoons fresh cilantro, very well chopped

3 Tablespoons your best extra virgin olive oil

2 Tablespoons, fresh lime juice

1 Pinch Salt, 1 pinch black pepper and 1 pinch chili flakes

1 cup pitted dates, coarsely chopped or sliced

8 ounces goat cheese, crumbled

2 or 3 fresh garlic cloves, mashed into the dressing

4 teaspoons well-toasted black sesame seeds

2 Tablespoons toasted flax seeds (optional toasting)

 

Take an up close look at each shred of red cabbage. You’ll see that each one has a surface covered with oil. As a result, the cabbage won’t clump together, as it would, if not made slippery with the olive oil. ©Joyce Hays, Target Health Inc.

 

Thinly slice the red cabbage on a mandolin. As you know, extremely sharp, so be careful and don’t let your kids use it. ©Joyce Hays, Target Health Inc.

 

Directions

1. Do all your chopping, slicing, toasting, cutting first.

2. In the salad bowl you’ll use for serving, add the olive oil, lime juice, pinch salt & black pepper, and with a fork, mash the two fresh garlic cloves. Also, add the chili flakes and with the fork, stir the dressing together.

3. Next, add all the cabbage and toss it so that every single piece of cabbage is covered with the dressing. Do this before you add anything else. It’s extremely important to do this now and not later. If you don’t cover each piece of cabbage now with the oil, the drier pieces will clump together and won’t toss well later.

 

Toasting all the black sesame seeds in my smallest pan. ©Joyce Hays, Target Health Inc. ©Joyce Hays, Target Health Inc.

 

4. Next, add half of the chopped dates, half of the crumbled cheese, half of the cilantro, half of the flax and black sesame seeds and toss the dressed cabbage, slowly.

Chopping the dates. ©Joyce Hays, Target Health Inc.

 

Chopping the cilantro. ©Joyce Hays, Target Health Inc.

 

5. Finally, sprinkle the salad with the remaining dates, cheese, cilantro and sesame seeds and serve.

6. If you want this salad to be less crunchy, let it sit for a while and the cabbage will soften up a bit.

 

We were recently at Ralph Lauren’s restaurant in midtown Manhattan, (East 50s, so, great for pre-theater dinner), and after ordering a salad, I asked about its wonderful crunch and learned that if you add some baked, very hard bread crumbs, pulverized in a food processor, to toasted black sesame seeds, you will get a pleasing crunch along with the flavor, that’s very satisfying. Might want to try that with this salad recipe or others.

If you bought a mandolin, but it’s turned into a dust gatherer, now you have an excellent reason to use it. There are certain tools that you cannot do without in a 21st Century kitchen, a mandolin is one of them and a food processor is another; a small kitchen scale also comes to mind.

 

In this colorful red cabbage salad, every one of the ingredients adds to the final extremely delicious flavor. I’ve experimented a lot with this recipe and you cannot omit any of these ingredients. I would even go so far as to say, don’t even substitute. Wait until you’re able to include all of them. If you don’t have black sesame seeds, don’t use white, order the black online. I get mine from Whole Foods, Amazon, FreshDirect and Nuts.com. All the other ingredients are readily available in an urban location. Considering, the extremely positive outcome, this is an easy recipe. Just a matter of following a few clear steps.

 

For dessert, we had apple circles cooked in dark brown sugar and brandy. Still working on this; will share when ready. ©Joyce Hays, Target Health Inc.

 

Here’s a pricy Italian red, 2012 Tignanello, from the renown Antinori Vineyards. This Tuscan red packs a wallop that captures your nose, tingles your palate and satisfies with a long warm finish. ©Joyce Hays, Target Health Inc.

 

We saw a different type of play this weekend at one of our theater clubs, where we are patrons, the well known, Manhattan Theater Club, called: Cost of Living. There were two disabled characters (out of four actors) in this drama, played by two actors with those same disabilities. I liked having handicapped actors in those roles. During the play and before the curtain call, you could not tell whether or not the actors were disabled, or acting disabled. It was moving during curtain calls, to see that one young female actor, really had both legs amputated from the knees down, and appeared with her prosthetic legs. There were several themes in this play, certainly one was, “who’s in control,“ and being handicapped does not mean being out of control.

 

We had a long lazy stretch of a welcomed extended weekend and managed to stay out of the sun. Hope you were rested too.

 

From Our Table to Yours

Bon Appetit!