The Future of the CRO Business

 

While outsourcing by pharmaceutical and device companies expands, there may be some shifts in the air. Last week we attended and participated on 2 panels at a meeting in Cambridge, MA on Clinical Trial Collaborations, sponsored by the Conference Forum. The meeting was co-chaired by our colleagues Ken Getz, Director of Sponsored Research Programs, Tufts CSDD and Katherine Vandebelt, Global Head, Clinical Innovation, Eli Lilly and Company, and was attended by more than 100 enthusiasts including global CRO and Industry executives. While a key theme was how to build and maintain relationships among study teams, there was a lot of discussion about reduced on-site monitoring as eSource systems such as direct data entry at the time of the office visit and integration with the EHR become adopted, and what happens when mobile devices and telemedicine arrive. There was also discussion about bringing back some data management activities in-house and the need for central storage of study documents.

 

Springtime in NY

 

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On the way to opera down Park Ave.  ©Target Health Inc.

 

ON TARGET is the newsletter of Target Health Inc., a NYC – based, full – service, contract research organization (eCRO), providing strategic planning, regulatory affairs, clinical research, data management, biostatistics, medical writing and software services to the pharmaceutical and device industries, including the paperless clinical trial.

 

For more information about Target Health contact Warren Pearlson (212-681-2100 ext. 165). For additional information about software tools for paperless clinical trials, please also feel free to contact Dr. Jules T. Mitchel or Ms. Joyce Hays. The Target Health software tools are designed to partner with both CROs and Sponsors. Please visit the Target Health Website.

 

Joyce Hays, Founder and Editor in Chief of On Target

Jules Mitchel, Editor

 

QUIZ

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Cryptosporidiosis

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Very high magnification micrograph of cryptosporidiosis cryptosporidium infection). H&E stain. Colonic biopsy. Source: Nephron – Own work, CC BY-SA 3.0,

 

 

Ernest Edward Tyzzer (1875-1965) was an American physician and parasitologist, who first described the organism, cryptosporidiosis in 1907, and who recognized that it was a coccidian. Cryptosporidiosis, also known as crypto, is a parasitic 1) ___ caused by Cryptosporidium, a protozoan parasite in the phylum Apicomplexa. It affects the intestines of mammals and is typically an acute short-term infection. It is spread, mainly, through the fecal-oral route, often through contaminated water.

 

Human infection with cryptosporidium was first documented in 1976. Since that time, cryptosporidium has been recognized as a cause of gastrointestinal illness in both immunocompetent and immunodeficient people. Infection with cryptosporidium results in watery diarrhea associated with varying frequencies of abdominal cramping, nausea, vomiting, and fever. In immunocompetent people, cryptosporidiosis is a self-limited illness, but in those who are 2) ___, infection can be unrelenting and fatal. Infection occurs in a variety of settings; waterborne outbreaks of cryptosporidium infection have been documented in association with drinking water from a contaminated artesian well, untreated surface water, and filtered public water supplies. Cryptosporidiosis can also affect the respiratory tract in both immunocompetent (i.e., individuals with a normal functioning immune system) and immunocompromised (e.g., persons with HIV/AIDS) individuals, resulting in watery diarrhea with or without an unexplained cough. In immunocompromised individuals, the symptoms are particularly severe and can be fatal. Recent evidence suggests that it can also be transmitted via fomites in respiratory secretions. Fomite is a term for any inanimate object that can carry disease-causing organisms. Towels, bedding used by a person with an illness, or just the transfer of bacteria on a kitchen cutting board, kitchen sink, a public toilet, public railing or bannister, cat sand box, animal or human hair, etc. Consider forensic medicine and the clues that epidemiologists look for, those items are often 3) ___.

 

Cryptosporidium is the organism most commonly isolated in HIV-positive patients presenting with diarrhea. Despite not being identified until 1976, it is one of the most common waterborne diseases and is found worldwide. The parasite is transmitted by environmentally hardy microbial cysts (oocysts) that, once ingested, exist in the small intestine and result in an infection of intestinal epithelial 4) ___. Cryptosporidiosis may occur as an asymptomatic infection, an acute infection (i.e., duration shorter than 2 weeks), recurrent acute infections in which symptoms reappear following a brief period of recovery for up to 30 days, and a chronic infection (i.e., duration longer than 2 weeks) in which symptoms are severe and persistent. It may be 5) ___ in individuals with a severely compromised immune system.

 

Cryptosporidium is a genus of protozoan pathogens which is categorized under the phylum Apicomplexa. Other apicomplexan pathogens include the malaria parasite Plasmodium, and Toxoplasma, the causative agent of 6) ___. Cryptosporidium is capable of completing its life cycle within a single host, resulting in microbial cyst stages that are excreted in feces and are capable of transmission to a new host via the fecal-oral route. Other vectors of disease transmission also exist. DNA studies suggest a relationship with the gregarines rather than the coccidia. The taxonomic position of this group has not yet been finally agreed upon. The genome of Cryptosporidium parvum was sequenced in 2004 and was found to be unusual among Eukaryotes in that the mitochondria seem not to contain DNA. A closely related species, C. hominis, also has its genome sequence available. CryptoDB.org is a NIH-funded database that provides access to the Cryptosporidium genomics data sets. Infection is through contaminated material such as earth, water, uncooked or cross-contaminated food that has been in contact with the feces of an infected individual or animal. Contact must then be transferred to the mouth and swallowed. It is especially prevalent amongst those in regular contact with bodies of fresh water including recreational water such as swimming 7) ___. Other potential sources include insufficiently treated water supplies, contaminated food, or exposure to feces. The high resistance of Cryptosporidium oocysts to disinfectants such as chlorine bleach enables them to survive for long periods and still remain infective. Cases of cryptosporidiosis can occur in a city that does not have a contaminated water supply. In a city with clean water, it may be that cases of cryptosporidiosis have different origins. Testing of water, as well as epidemiological study, are necessary to determine the sources of specific infections. Note that Cryptosporidium typically does not cause serious or fatal illness in healthy people. It may chronically sicken some children, as well as adults who are exposed and immunocompromised. As few as 2 to 10 oocysts can initiate an infection. The parasite is located in the brush border of the epithelial cells of the small intestine. They are mainly located in the jejunum. When the sporozoites attach the epithelial cells’ membrane envelops them. Thus, they are “intracellular but extracytoplasmic“. The parasite can cause damage to the microvilli where it attaches. The immune system reduces the formation of Type 1 merozoites as well as the number of thin-walled oocysts. There are many diagnostic tests for Cryptosporidium. They include microscopy, staining, and detection of antibodies.

 

Many treatment plants that take raw water from rivers, lakes, and reservoirs for public drinking water production use conventional filtration technologies. This involves a series of processes, including coagulation, flocculation, sedimentation, and filtration. Direct filtration, which is typically used to treat water with low particulate levels, includes coagulation and filtration, but not sedimentation. Other common filtration processes, including slow sand filters, diatomaceous earth filters and membranes will remove 99% of Cryptosporidium. Membranes and bag and cartridge filters remove Cryptosporidium product-specifically. While Cryptosporidium is highly resistant to chlorine disinfection, with high enough concentrations and contact time, Cryptosporidium will be inactivated by chlorine dioxide and ozone treatment. The required levels of chlorine generally preclude the use of chlorine disinfection as a reliable method to control Cryptosporidium in drinking water. Ultraviolet (UV) light treatment at relatively low doses will inactivate Cryptosporidium. Water Research Foundation-funded research originally discovered 8) ___ efficacy in inactivating Cryptosporidium. One of the largest challenges in identifying outbreaks is the ability to identify Cryptosporidium in the laboratory. Real-time monitoring technology is now able to detect Cryptosporidium with online systems, unlike the spot and batch testing methods used in the past. The most reliable way to decontaminate drinking water that may be contaminated by Cryptosporidium is to boil it. In the US the law requires doctors and labs to report cases of 9) ___ to local or state health departments. These departments then report to the Center for Disease Control and Prevention. The best way to prevent getting and spreading cryptosporidiosis is to have good hygiene and sanitation. An example would be hand-washing. Prevention is through washing hands carefully after going to the bathroom or contacting stool, and before eating. People should avoid contact with animal feces. They should also avoid possibly contaminated food and water. Standard water filtration may not be enough to eliminate Cryptosporidium; boiling for at least 1 minute (3 minutes above 6,500 feet (2,000 m) of altitude) will decontaminate it. Heating milk at 71.7 0C (161 0F) for 15 seconds pasteurizes it and can destroy the oocysts’ ability to infect. Water can also be made safe by filtering with a filter with pore size not greater than 1 micrometer, or by filters that have been approved for “cyst removal“ by NSF International National Sanitation Foundation. Bottled drinking water is less likely to contain Cryptosporidium, especially if the water is from an underground source. The US CDC notes the recommendation of many public health departments to soak contaminated surfaces for 20 minutes with a 3% hydrogen peroxide (99% kill rate) and then rinse them thoroughly, with the caveat that no disinfectant is guaranteed to be completely effective against Cryptosporidium. However, hydrogen peroxide is more effective than standard bleach solutions.

 

Symptomatic treatment primarily involves fluid rehydration, electrolyte replacement (sodium, potassium, bicarbonate, and glucose), and antimotility agents (e.g. loperamide). Supplemental zinc may improve symptoms, particularly in recurrent or persistent infections or in others at risk for zinc deficiency. Cryptosporidiosis is found 10) ___ and causes 50.8% of water-borne diseases that are attributed to parasites. In developing countries, 8-19% of diarrheal diseases can be attributed to Cryptosporidium and 10% of the population excretes oocysts. In developed countries, the number is 1-3%. The age group most affected is children from 1 to 9 years old. As of 2010 cryptosporidiosis caused about 100,000 deaths down from 220,000 in 1990. Roughly 30% of adults in the United States are seropositive for cryptosporidiosis, meaning that they contracted the infection at some point in their lives.

 

ANSWERS: 1) disease; 2) immunocompromised; 3) fomites; 4) tissue; 5) fatal; 6) toxoplasmosis; 7) pools; 8) UV’s; 9) cryptosporidiosis; 10) worldwide

 

Public Health: Milwaukee Public Drinking Water Disaster 1993

 

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Life cycle of Cryptosporidium spp. Sources: CDC/Alexander J. da Silva, PhD/Melanie Moser (PHIL #3386), 2002 – CDC Public Health Image Library, Public Domain

 

 

In April 1993, Milwaukee, Wisconsin suffered the largest waterborne disease outbreak in U.S. history – 100 people died and 403,000 were sickened. At that time, Milwaukee was served by two water treatment plants that used raw water from Lake Michigan. When people started complaining about the odor and taste of their tap water, calls began flooding the Milwaukee Health Department. The water treatment plants had just passed inspection and tests for bacteria and viruses came up blank. Before the outbreak, severe spring storms, flooding caused the lake’s turbidity and bacterial counts to rise dramatically. During the outbreak, effluent produced by one plant had a turbidity approaching 2.5 ntu, a high reading that indicated an increase in particulates passing through the plant. The increase may have also meant an increase in passage of Cryptosporidium oocysts.

 

On April 5, 1993, the Wisconsin Division of Health was contacted by the Milwaukee Department of Health after reports of numerous cases of gastrointestinal illness that had resulted in widespread absenteeism among hospital employees, students, and schoolteachers. Little information was available about the nature of the illness or the results of laboratory tests of stool specimens from those who were ill. On April 7, two laboratories identified cryptosporidium oocysts in stool samples from seven adult residents of the Milwaukee area; none of the laboratories surveyed had found evidence of increased or unusual patterns of isolation of any other enteric pathogen.

 

The Milwaukee Water Works (MWW), which obtains water from Lake Michigan, supplies treated water to residences and businesses in the City of Milwaukee and nine surrounding municipalities in Milwaukee County. Either of two water-treatment plants, one located in the northern part of the city, and the other in the southern part, can supply water to the entire district; however, when both plants are in operation, the southern plant predominantly serves the southern portion of the district. Examination of the two plants’ records on the quality of untreated water (intake) and treated water (that supplied to customers) revealed an increase in the turbidity of treated water from the southern plant, beginning approximately on March 21, with increases to unprecedented levels of flooding from March 23 through April 5. These findings pointed to the water supply as the likely source of infection and led to the institution, on the evening of April 7, of an advisory to MWW customers to boil their water. The southern plant was temporarily closed on April 9. The policies, procedures, and physical plant of the southern MWW facility were reviewed and inspected in April 1993. Water that had been frozen and stored by a southern Milwaukee company in 213-liter blocks on March 25 and April 9, 1993, was melted and examined for cryptosporidium oocysts with an immunofluorescent technique. Medical examination for enteric pathogens was begun among 14 clinical laboratories in Milwaukee County. The laboratories reported the retrospective and prospective test results for all stool specimens submitted for bacterial or viral culture and examination for ova and parasites and for bacterial culture. Bacteria for salmonella, shigella, campylobacter, and cryptosporidium were found. Specimens were examined by electron microscopy. Serum samples obtained during the acute and convalescent phases of illness in residents were tested for antibody to the Norwalk virus. Bacterial cultures for yersinia and aeromonas were positive. During the same medical evaluation, specimens examined for ova and parasites were found to have giardia, and specimens cultured for enteric viruses were positive, including rotavirus.

 

To collect data, telephone calls and surveys were made to patients and questionnaires (long and short) were distributed to collect information on demographic characteristics and clinical illness. Questions were also asked about preexisting chronic diseases, weight loss, recurrent diarrhea, and length of hospital stay. People were considered to be immunocompromised if they reported having had a positive test for the human immunodeficiency virus or if they were being treated with immunosuppressive drugs, cancer chemotherapy, radiation therapy, or renal dialysis. Telephone surveys were also done to determine the extent of the outbreak of disease. At the time of the outbreak, both of Milwaukee’s water treatment plants treated water by adding chlorine and polyaluminum chloride (a coagulant to enhance the formation of larger particulates), rapid mixing, mechanical flocculation (which promotes the aggregation of particulates to form floc), sedimentation, and rapid sand filtration. After filtration, the effluent (treated water) was stored in a large clear well until it was supplied to customers. Filters were cleaned by backwashing them with water, which was then recycled through the treatment process. Water obtained by melting ice blocks contained cryptosporidium. When samples were sent to the Centers for Disease Control and Prevention, oocysts examined by the CDC were 4 to 6 micrometers in diameter and were positive for cryptosporidium with monoclonal-antibody staining. In general, the frequencies of signs and symptoms of illness were similar in immunocompromised and immunocompetent patients. However, the immunocompromised patients had more diarrhea per day. By limiting the case definition to watery diarrhea in surveys taken, the size of the affected population (403,000), was probably underestimated.

 

Despite communitywide increases in diarrheal illness in Milwaukee, the recognition of cryptosporidium infection as the cause of this outbreak was delayed for several reasons. The constellation of gastrointestinal symptoms (e.g., diarrhea, abdominal cramping, and nausea) and constitutional signs and symptoms (e.g., fatigue, low-grade fever, muscle aches, and headaches) reported by Milwaukee-area residents led many physicians to diagnose viral gastroenteritis or “intestinal flu,“ without further investigation. Our findings suggest that people with diarrhea seek health care infrequently, do so only when the illness is severe or prolonged, and are unlikely to be tested for cryptosporidium infection. Unlike the detection of other intestinal parasites, which are identified by means of a standard examination for ova and parasites, the detection of cryptosporidium requires special testing. Infrequent testing for cryptosporidium in patients with diarrhea may be due to misconceptions about the incidence and severity of this infection among immunocompetent patients. In the Milwaukee outbreak, cryptosporidium oocysts in untreated water from Lake Michigan apparently entered the southern water-treatment plant and were then inadequately removed by the coagulation and filtration process. Cryptosporidium oocysts have often been found in untreated surface water used for public water supplies in the United States. The sources of the oocysts leading to the outbreak in Milwaukee and the timing of their entrance into Lake Michigan include, cattle along two rivers that flow into the Milwaukee harbor, slaughterhouses, and human sewage. Rivers that were swelled by spring rains and snow runoff, causing flooding, may have transported oocysts into Lake Michigan and from there to the intake of the water treatment plants.

 

Because some visitors to the MWW service area who drank very small amounts of water (<240 ml [8 oz]) had laboratory-confirmed cryptosporidiosis, the peak concentration of oocysts in the water probably far exceeded one oocyst per liter. Thus, the concentration of cryptosporidium oocysts found in the tested ice vastly underestimates the peak level in water. The number of both laboratory-confirmed and clinically defined cases of cryptosporidium infection with an onset of illness was higher than expected, suggesting that cryptosporidium oocysts had entered the water supply before the increase in turbidity was apparent. Cryptosporidiosis is an underdiagnosed condition, and outbreaks are likely to be under recognized. Plant design and water-treatment procedures should be improved to maintain the quality of treated water at a level that will make the presence of oocysts unlikely (e.g., a goal of turbidity <0.1 NTU). It has been recommended that clinicians and laboratories consider performing routine tests for cryptosporidium in people with watery diarrhea and that public health officials make cryptosporidium infection a reportable condition. In the United Kingdom, water and health officials have already developed an extensive strategy to investigate the clinical importance of cryptosporidium found in water supplies. Intensive efforts and cooperation between the medical community and those who provide and regulate drinking water in the United States will be required to prevent future waterborne outbreaks caused by this emerging pathogen and ensure the safety of drinking water for all citizens.

 

Sources: NEJM, CDC.gov, NIH.gov, EPA.gov; Division of Parasitic Diseases, Center for Infectious Diseases; Roger Glass, M.D., M.P.H., Ph.D., Stephan S. Monroe, Ph.D., Charles Humphries, Ph.D., and Sara Stine, Centers for Disease Control and Prevention (CDC) Viral Gastroenterology Laboratory; Margaret Hurd and the staff of the CDC Parasitology Laboratory; the staff of the Wisconsin State Laboratory of Hygiene; the staff of the Survey Research Laboratory, University of Wisconsin Extension; Darren Lytle, P.E., U.S. Environmental Protection Agency; and Ava Navin, Epidemiology Program Office, CDC.

 

Milwaukee Water Disaster 1993

 

Mindfulness Meditation and Relief For Low-Back Pain

 

Mindfulness based stress reduction (MBSR) brings together elements of mindfulness meditation and yoga while cognitive-behavioral therapy (CBT) is a form of psychotherapy that trains individuals to modify specific thoughts and behaviors. Mindfulness-based stress reduction (MBSR) has not been rigorously evaluated for young and middle-aged adults with chronic low back pain. As a result, a study published in the Journal of the American Medical Association (2016;315:1240-1249) was performed to evaluate the effectiveness for chronic low back pain of MBSR vs cognitive behavioral therapy (CBT) or usual care.

 

The study was a randomized, interviewer-blind, clinical trial which included 342 adults aged 20 to 70 years with chronic low back pain randomly assigned to receive MBSR (n=116), CBT (n=113), or usual care (n=113). Treatments were delivered in 8 weekly 2-hour groups. Usual care included whatever care participants received. The main outcome measures were the co-primary outcomes of the percentages of participants with clinically meaningful (>30%) improvement from baseline in functional limitations (modified Roland Disability Questionnaire [RDQ]; range, 0-23) and in self-reported back pain bothersomeness (scale, 0-10) at 26 weeks. Outcomes were also assessed at 4, 8, and 52 weeks.

 

Of the 342 randomized participants, the mean age was 49.3 (range 20-70) years, 224 (65.7%) were women and the mean duration of back pain was 7.3 years (range, 3 months-50 years), 123 (53.7%) attended 6 or more of the 8 sessions, 294 (86.0%) completed the study at 26 weeks, and 290 (84.8%) completed the study at 52 weeks. In intent-to-treat analyses at 26 weeks, the percentage of participants with clinically meaningful improvement on the RDQ was higher for those who received MBSR (60.5%) and CBT (57.7%) than for usual care (44.1%) (P=0.04; The percentage of participants with clinically meaningful improvement in pain bothersomeness at 26 weeks was 43.6% in the MBSR group and 44.9% in the CBT group, vs 26.6% in the usual care group (overall P=0.01). Findings for MBSR persisted with little change at 52 weeks for both primary outcomes.

 

The authors concluded that among adults with chronic low back pain, treatment with MBSR or CBT, compared with usual care, resulted in greater improvement in back pain and functional limitations at 26 weeks, with no significant differences in outcomes between MBSR and CBT. However, since findings for MBSR persisted with little change at 52 weeks for both primary outcomes, the findings suggest that MBSR may be an effective treatment option for patients with chronic low back pain.

 

According to the NIH, it is vital that effective non-pharmacological treatment options be identified if at all possible for the 25 million people who suffer from daily pain in the United States and that results from this study affirm that non-drug/non-opioid therapies, such as meditation, can help manage chronic low-back pain, and that physicians and their patients can use this information to inform treatment decisions.

 

Couples’ Pre-Pregnancy Caffeine Consumption Linked to Miscarriage Risk

 

According to a study published online in Fertility and Sterility (22 March 2016), a study was performed to estimate pregnancy loss incidence in a contemporary cohort of couples whose lifestyles were measured during sensitive windows of reproduction to identify factors associated with pregnancy loss for the continual refinement of preconception guidance. For the study, the authors analyzed data from the Longitudinal Investigation of Fertility and the Environment (LIFE) Study, which was established to examine the relationship between fertility, lifestyle and exposure to environmental chemicals.

 

This was a prospective cohort with preconception enrollment performed in 16 counties in Michigan and Texas, with 344 couples with a singleton pregnancy followed daily through 7 post-conception weeks of gestation. The study tracked the couples’ daily recorded use of cigarettes, caffeinated and alcoholic beverages, and multivitamins and each women used fertility for ovulation detection and digital pregnancy tests. Pregnancy loss was denoted by conversion to a negative pregnancy test, onset of menses, or clinical confirmation depending upon gestation. Using proportional hazards regression and accounting for right censoring, the authors estimated adjusted hazard ratios and 95% confidence intervals (aHR, 95% CI) for couples’ lifestyles (cigarette smoking, alcoholic and caffeinated drinks, multivitamins) during three sensitive windows: preconception, early pregnancy, and peri-conception. The main outcome measures were incidence and risk factors for pregnancy loss.

 

Results showed that 98/344 (28%) women with a singleton pregnancy experienced an observed pregnancy loss. In the preconception window, loss was associated with female age >35 years (aHR = 1.96) accounting for couples’ ages, women’s and men’s consumption of >2 daily caffeinated beverages (aHR 1.74 and 1.73, respectively), and women’s vitamin adherence (aHR 0.45,). The findings were similar for lifestyle during the early pregnancy and peri-conception windows.

 

According to the authors, a woman is more likely to miscarry if she and her partner drink more than two caffeinated beverages a day during the weeks leading up to conception, and similarly, women who drank more than two daily caffeinated beverages during the first seven weeks of pregnancy were also more likely to miscarry. However, women who took a daily multivitamin before conception and through early pregnancy were less likely to miscarry than women who did not.

 

Human Factors and Combination Products

 

The following is based on a post on FDA Voice

 

Combination products combine a drug, device, and/or biological product (referred to as “constituent parts“) with one another, and represent an important and growing category of therapeutic and diagnostic products under the FDA’s regulatory authority. These products, come in three basic configurations: their constituent parts may be physically or chemically combined; they may be co-packaged; or they may be separately distributed with specific labeling that provides instructions for their combined use. The different constituent parts of a combination product can add complexity to the final product. For example, when a medical device is part of the combination product, issues that relate to how the product is used can be as important as the product itself.

 

Human factors engineering, and the closely related field of usability engineering, both study how people interact with technology, to understand how the design of user interfaces for technology affects the quality, experience, and outcomes of that interaction. The questions addressed by human factors studies overlap with those addressed by “medication error“ assessments, another area of user-product interaction evaluation commonly applied to drugs. The understanding gained from these evaluations can be applied to the design and review of the user interfaces for FDA-regulated products to assure their safety and effectiveness.

 

Because the design of a combination product can have a significant impact on whether a given product is safe and effective for its intended use, human factors evaluations are a central consideration for FDA when it assesses combination products, particularly those that include certain devices. In February 2016, FDA published a draft guidance entitled “Human Factors Studies and Related Clinical Study Considerations in Combination Product Design and Development.“ This draft guidance builds on principles articulated in earlier guidances that discuss human factors and medication error considerations for medical devices and drugs. When final, it will represent FDA’s thinking on when and how combination product manufacturers should perform human factors evaluations for investigational or marketing applications. The draft guidance provides examples of combination products that include devices and describes recommendations for how to approach human factors studies for them, focusing on key challenges for developers such as:

 

The timing and sequencing of human factors studies in relation to overall development and study of a combination product;

How human factors studies compare with and relate to other types of clinical studies;

When changes to a combination product call for new human factors studies to be performed;

The role of simulated-use versus actual-use human factors studies; and

What information should be provided to the FDA, and when, to ensure timely feedback for a human factors study.

During the comment period which closes on May 3, 2016, FDA is seeking input on the overall guidance, as well as requesting that stakeholders submit examples of combination products in their comments and address whether they believe human factors studies are needed for them. FDA is also seeking input on what challenges and development risks may arise if such studies are conducted before, in parallel to, or after major clinical studies for combination products. Input from stakeholders will help inform FDA’s final guidance in this important area. FDA is developing additional guidance for combination products, including current good manufacturing practices and a final rule on postmarket safety reporting.

 

Parmesan Roasted Asparagus with Garlic & Fresh Lemon

 

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Ingredients

 

2 1/2 pounds fresh organic asparagus (about 20 to 30 large ones)

2 Tablespoons extra virgin olive oil

Pinch salt

Pinch black pepper

1/2 to 1 cup freshly grated Parmesan

Pinch chili flakes

10 to 20 fresh garlic cloves, sliced (not thin slices)

Zest from 1 lemon

1 fresh lemon, juiced

2 lemons cut in wedges, or circles, for serving

 

 

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Get fat asparagus, not the thin ones. Try to find organic, locally grown produce. ©Joyce Hays, Target Health Inc.

 

 

Advice on Ingredients

 

There are so few ingredients in this recipe, that you want to be sure you get the very best.

First of all, only use the nice fat asparagus, and not the thin ones. The fat ones roast better. Spring is the season for asparagus, so if you can get locally grown, that’s the best.

Use fresh garlic and not garlic powder or garlic salt.

Use fresh lemon juice and not bottled.

Grate the parmesan yourself; it’s easy and makes a difference.

As for olive oil: there’s been a scandal going on in Europe regarding olive oil, so for every cooking need, only use extra virgin olive oil. The FDA does inspect extra virgin olive oil, to be sure there are no cheaper oils added, which is what has been going on in Europe. I have started using only California extra virgin olive oil. A these days, I am switching to as many organic items as are available.

 

Directions

 

Preheat the oven to 400 degrees.

Grate the parmesan and set aside.

 

 

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For a better flavor, grate the parmesan yourself. ©Joyce Hays, Target Health Inc.

 

 

 

Wash the asparagus well. Even if it’s organic, you don’t know who has been handling it. It’s a good example of a fomite.

Cut one inch off the bottom of each asparagus stalk. Or just break off the bottom inch. It usually breaks, with a nice crisp sound, at just the right point. Then with a potato peeler, peel just a little from the bottom of each stalk, just to be sure you get all the tough fibers off the bottom of the stalk.

Cover a baking sheet with parchment. It just makes cleaning up easier, when you throw it out later. This is optional.

Drizzle extra virgin olive oil on a baking sheet. Add the juice from one lemon and the zest from one lemon and stir it into the olive oil. Add the salt, pepper and chili flakes and stir into the lemon/oil mixture.

 

 

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Parchment on a baking sheet. Look at how the bottom of the stalks are treated. Just a few strokes of a veggie peeler to remove any tough fibers. ©Joyce Hays, Target Health Inc.

 

 

Lay all the asparagus in a single layer on the baking sheet. Roll the asparagus around, so they get covered with the lemon juice and olive oil. Distribute all the slices of garlic over the asparagus stalks.

 

 

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About to roll the asparagus around to get them covered with the extra virgin olive oil mixture. ©Joyce Hays, Target Health Inc.

 

 

Drizzle more olive oil over the asparagus and the garlic and put in oven to roast.

Roast for 15 to 20 minutes, until tender.

 

 

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Going into the oven. ©Joyce Hays, Target Health Inc.

 

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Here they are after roasting for 20 minutes, the aroma is fabulous! ©Joyce Hays, Target Health Inc.

 

 

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They’ve roasted for 20 minutes, now sprinkle as much, or as little freshly grated Parmesan over the asparagus, as you wish, and roast for 5 more minutes. ©Joyce Hays, Target Health Inc.

 

 

Open oven door, pull the baking sheet out so you can sprinkle the roasted asparagus with the Parmesan. Put back in oven and roast for another 1 minute, just to melt the cheese.

 

 

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Everything has caramelized. Roasted garlic is now crunchy and sweet and the aroma is even more heightened. With a large flat spatula, transfer the asparagus to a nice serving platter and serve right away, while it’s nice and warm and juicy. There’s nothing like young tender asparagus, when it’s in season. ©Joyce Hays, Target Health Inc.

 

 

Serve right away with lemon wedges.

 

 

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We’re getting into a veggie mode, more and more. We love fresh vegetables, cooked in a simple delicious way, like the asparagus above. Hope you’ll try this recipe; it’s simple and easy to make; not to mention how gratifying it is to make something like this, and sit down and enjoy it with someone. We had chilled Pino Grigio with the meal. ©Joyce Hays, Target Health Inc.

 

 

We started with a newer version of my green bean salad, which I will share soon, and icy Pinot Grigio. Next we had the roasted asparagus with garlic and parmesan plus a new potato recipe I’m trying out. The potato recipe is so easy to make and yet one of the most delicious potato dishes I’ve put together, that this is another one I will be sharing soon. For dessert we nibbled on Cara Cara oranges and left-over chocolate rum cake with marzipan.

 

This weekend we went to the MetOpera, one of our favorite weekend destinations. The opera was The Marriage of Figaro (Mozart), a new production, and sorry to say, disappointing. The voices were not up to what we were expecting, also we become very expectant when there’s a new production, but these sets were dismal, like so many of the Met’s new sets – dark and dismal. The Met had the technology, that is a huge computerized carousel, that a large number of sets can be installed on, with set changes easily turned, giving a set designer an enormous advantage; also, easy removal of one set for another. We go to so much theater in Manhattan, that we see tiny (by comparison with the MetOpera) theater clubs’ gorgeous set designs, week after week. For example, at a small theater club where we are patrons, The Atlantic Theater Club in Chelsea on West 20th Street, a little church was gutted and a cozy theater constructed within the walls of the old church. A small computerized carousel was installed on the stage, permitting in the last production, a total of eight different beautifully designed sets. As the carousel turned with its set changes, it was stunning to behold one perfect set after another. It is beyond belief, how and why a small theater club with limited budget is able to come up with sound, light and set design of the highest professional caliber, missing from the world famous MetOpera.

 

However, we may complain about the MetOpera, where we are also patrons, we still love going there and hope that enough people feel the way we do, and that changes will be made. Below are three videos from Marriage of Figaro, unfortunately, not from the production this past Saturday.

 

Overture to Marriage of Figaro

 

Renee Fleming: Mozart – Le Nozze di Figaro, ?E Susanna non vien! Dove sono i bei momenti’

 

Marriage of Figaro, Finale

 

 

20160328-11

Happy Spring Everyone! All the lovely pastel colors of Spring are

starting to appear in our neighborhood. ©Joyce Hays, Target Health Inc.

 

 

 

From Our Table to Yours !

 

Bon Appetit!