New Publication on Risk-based Monitoring

 

Applied Clinical Trials has just published a very exciting article by the eClinical Forum Risk Based Monitoring Taskforce on the topic of best practices for risk-based monitoring. Congratulations to Darlene Kalinowski from BMS who took the lead on this project.

 

The article was coauthored by Dean Gittleman and Jules Mitchel from Target Health and our colleagues from Allergan, Array BioPharma, BMS, Eli Lilly, Novartis, Perceptive Informatics, Pharmapros, PPD, and Quintiles.

 

For everyone’s convenience, Target Document was used for the management of the manuscript drafts. All authors received an alert from the website when a document was “checked out“ and another alert when it was checked back in. As a result, the manuscript could not be worked on by 2 people at the same time and all versions of the manuscript were maintained so if needed, it was easy to go back to previous work efforts.

 

For more information about Target Health contact Warren Pearlson (212-681-2100 ext. 104). For additional information about software tools for paperless clinical trials, please also feel free to contact Dr. Jules T. Mitchel or Ms. Joyce Hays. The Target Health software tools are designed to partner with both CROs and Sponsors. Please visit the Target Health Website.

Gut Bacteria from Thin Humans Can Slim Mice Down — Next Humans?

 

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Dr. Jeffrey I. Gordon, left, and Vanessa K. Ridaura are two members of a scientific team whose research shows a connection between human gut bacteria and obesity.

 

 

The trillions of bacteria that live in the gut – helping digest foods, making some vitamins, making amino acids – may help determine if a person is fat or 1) ___. The evidence is from a novel experiment involving mice and humans that is part of a growing fascination with gut bacteria and their role in health and diseases like irritable bowel 2) ___ and Crohn’s disease. In this case, the focus was on obesity. Researchers found pairs of human twins in which one was obese and the other lean. They transferred gut bacteria from these twins into mice and watched what happened. The mice with bacteria from fat twins grew fat; those that got bacteria from lean twins stayed lean.

 

The study, published online, September 5, 2013, by the journal Science, is “pretty striking,“ said Dr. Jeffrey S. Flier, an obesity researcher and the dean of the Harvard Medical School, who was not involved with the study. “It’s a very powerful set of experiments.“ Michael Fischbach of the University of California, San Francisco, who also was not involved with the study, called it “the clearest evidence to date that gut bacteria can help cause 3) ___.“ “I’m very excited about this,“ he added, saying the next step will be to try using 4) ___bacteria to treat obesity by transplanting feces from thin people. “I have little doubt that this will be the next thing that happens,“ Dr. Fischbach said.

 

But Dr. Flier said it was far too soon for that. “This is not a study that says humans will have a different body 5) ___“ if they get a fecal transplant, he said. “This is a scientific advance,“ he added, but many questions remain. Dr. Jeffrey I. Gordon of Washington University in St. Louis, the senior investigator for the study, also urged caution. He wants to figure out which 6) ___ are responsible for the effect, so that, eventually, people can be given pure mixtures of bacteria instead of feces. Or, even better, learn what the bacteria produce that induces thinness and give that as a treatment.

 

While gut bacteria are a new hot topic in medicine, he added that human biology is complex and that obesity in particular has many contributors, including 7) ___ and diet. In fact, the part of the study that most surprised other experts was an experiment indicating that, with the right diet, it might be possible to change the bacteria in a fat person’s gut so that they promote leanness rather than obesity. The investigators discovered that given a chance, and in the presence of a low-fat diet, bacteria from a lean twin will take over the gut of a mouse that already had bacteria from a fat twin. The fat mouse then loses weight. But the opposite does not happen. No matter what the 8) ___, bacteria from a fat mouse do not take over in a mouse that is thin.

 

Although researchers suspected that gut bacteria might play a role in human obesity, it has been difficult to get convincing evidence. While there are often differences in gut bacteria in fat and lean people, they could be a cause or an effect of obesity. And gut bacteria vary from individual to individual, making it very difficult to decide which, if any, affect 9) ___ weight. Those obstacles led Dr. Gordon and his colleagues to look for those rare sets of twins in which only 10) ___ twin is fat. That allowed them to cancel out much of the effect of genetics and environment. They gave the twins’ fecal bacteria to mice that were born and reared in a sterile environment and had no bacteria of their own as a result. The mice were genetically identical, so genetic factors played no role in their weights. Five weeks after they got human gut bacteria, the mice with bacteria from the fat twins had about 15-17% more body fat than those that had bacteria from thin twins. They also had some of the metabolic changes associated with obesity. Next came what Dr. Gordon calls the “Battle of the Microbiota,“ referring to the collection of gut microbes. The researchers put mice with gut bacteria from lean twins in the same cage as mice with gut bacteria from obese twins. Mice housed together eat one another’s droppings, so the mice in the cage naturally end up sharing gut bacteria. He also put in germ-free11) ___ to determine which collection of gut bacteria they would get. Or would they get a mixture?

 

That led to the discovery that bacteria from the lean twins took over in the mice that started out with bacteria from the fat twins, resulting in weight loss and a correction of the metabolic abnormalities the mice had developed. But the mice were eating standard mouse food, which is very low in fat. Then Dr. Gordon’s colleague Vanessa K. Ridaura had an idea. From a national survey about what Americans eat, she and her colleagues determined the diets of those eating the most fruits and vegetables and the least saturated fats and the diets of those at the opposite end of the spectrum. With that information, they created mouse food pellets of the same two compositions by cooking and drying fruits and vegetables and combining them with fats in the right proportions. They then repeated the experiment, putting fat and lean mice together in a cage and giving them one of the two types of food. The fat mice that got food high in fat and low in fruits and vegetables kept the gut bacteria from the fat twins and remained fat. The thin twins’ gut bacteria took over only when the mice got pellets that were rich in fruits and 12) ___ and low in fat.

 

Dr. Gordon’s plan to isolate the bacteria or their products responsible for leanness “could take many decades,“ said Dr. Alexander Khoruts, a gastroenterologist at the University of Minnesota. “I am not down on this approach,“ Dr. Khoruts said, but added that it would be a lot quicker to try fecal 13) ___. They have worked in one situation: people with a terrible gut infection with the bacteria Clostridium difficile get better when given feces from healthy people. Those were people with no other treatment options, Dr. Karp noted, but, he said, perhaps obese people who have not done well after bariatric 14) ___ might be in the same desperate situation. “Maybe we could try it out very, very gingerly, very, very carefully,“ Dr. Karp said, noting that that was his personal opinion. But he added that he was not sure weight loss centers would take that cautious approach. “It would not surprise me if someone somewhere starts doing it,“ Dr. Karp said. Source: The New York Times, by GINA KOLATA, Published: September 5, 2013

 

ANSWERS: 1) thin; 2) syndrome; 3) obesity; 4) gut; 5) weight; 6) bacteria; 7) genetics; 8) diet; 9) body; 10) one; 11) mice; 12) vegetables; 13) transplants; 14) surgery

Frederick Griffith MD, Bacteriologist (1879-1941)

 

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Frederick Griffith MD

 

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In this image, a gene from bacterial cell 1 is moved from bacterial cell 1 to bacterial cell 2. This process of bacterial cell 2 taking up new genetic material is called transformation.

 

 

Frederick Griffith (1879-1941) was a British bacteriologist whose focus was the epidemiology and pathology of bacterial pneumonia. In January 1928 he reported what is now known as Griffith’s Experiment, the first widely accepted demonstrations of bacterial transformation, whereby a bacterium distinctly changes its form and function. Griffith showed that Streptococcus pneumoniae, implicated in many cases of lobar pneumonia, could transform from one strain into a different strain. The observation was attributed to an unidentified transforming principle or transforming factor. This was later identified as DNA. Griffith’s discovery was dramatic, in that a harmless strain of Streptococcus pneumoniae could be made virulent after being exposed to heat-killed virulent strains. Griffith hypothesized that some “transforming principle“ from the heat-killed strain was responsible for making the harmless strain virulent.

 

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Streptococcus pyogenes bacteria at 900x magnification.

 

 

America’s leading pneumococcal researcher, Oswald T. Avery, wrongly speculated that Griffith had failed to apply adequate controls. A cautious and thorough researcher, and a reticent individual, Griffith’s tendency was to publish only findings that he believed truly significant, and Griffith’s findings were rapidly confirmed by researchers in Avery’s laboratory. His discovery was one of the first to show the central role of DNA in heredity.

 

Fred Griffith was born in Hale, Cheshire county, England, in about 1879 (exact month/day uncertain), and attended Liverpool University. Thereafter, he worked at the Liverpool Royal Infirmary, the Joseph Tie Laboratory, and the Royal Commission on Tuberculosis. In 1910 Fred Griffith was hired by the local government board.

 

During World War I (1913-18), the local government board’s laboratory was assumed by the national government, namely UK government, and became the Ministry of Health’s Pathological Laboratory – where Griffith was medical officer. The UK government spent money sparingly on the laboratory, which remained very basic, though Griffith and his colleague, William M. Scott, “could do more with a kerosene tin and a primus stove than most men could do with a palace“.

 

Griffith was sent pneumococci samples taken from patients throughout the country, amassed a large number, and would type – in other words classify – each pneumococci sample to search patterns of pneumonia epidemiology, and Griffith experimented on mice for improved understanding of its pathology. Griffith performed the pivotal experiments – actually very many experiments – during the 1920s. With outbreak of World War II (1939-45), the laboratory was expanded into the Emergency Public Health Laboratory Service.

 

Griffith‘s Experiment

 

Pneumococci has two general forms – rough (R) and smooth (S). The S form, considered virulent, bears a capsule, which is a slippery polysaccharide coat – atop and outside the peptidoglycan cell wall common among all classical bacteria – enhances bacterial evasion of efficient phagocytosis by the host’s innate immune cells. Injected subcutaneously with S form, mice succumbed to pneumonia and death within a couple of days. The R form, however, lacking a capsule – its outer surface being cell wall – was considered a virulent, not prompting pneumonia.

 

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When Griffith injected heat-killed S into mice, as expected no disease ensued. When mice were injected with a mixture of heat-killed S and live R, however, pneumonia and death ensued. The live R had transformed into S – and replicated as such – often characterized as Griffith’s Experiment. More accurately, point six of Griffith’s abstract reports, that R tended to transform into S if a large amount of live R, alone, were injected, and that adding much heat-killed S made transformation reliable Griffith also induced some pneumococci to transform back and forth.

 

Griffith also reported transformation of serological type – bacterial antigenicity – distinct from presence or absence of a capsule. Bacteriologist Fred Neufeld, of the Robert Koch Institute in Berlin, Germany, had earlier identified the pneumococcal types, confirmed and expanded by Alphonse Dochez at Oswald Avery’s laboratory in America at The Rockefeller Hospital. Types I, II, and III were each a distinct antigenic grouping, whereas type IV was a catchall of varying antigenicities not matching other types. Illustrating S pneumoniaes plasticity, the abstract of Griffith’s paper reports, “The S form of Type I has been produced from the R form of Type II, and the R form of Type I has been transformed into the S form of Type II“.

 

Biomedical Reception

 

America’s most prominent pneumococcus expert, Oswald Avery, in New York at The Rockefeller Hospital – which opened in 1910 on The Rockefeller Institute’s campus – initially explained that Griffith’s experiments must have been poorly conducted and succumbed to contamination. Of course, Avery was wrong. Later, Avery biographer and colleague at The Rockefeller Institute, microbiologist Rene Dubos, recruited by The Rockefeller Institute from France, described Griffith’s findings as “exploding a bombshell in the field of pneumococcal immunology“. Griffith’s discovery was a huge contribution!

 

Avery’s associate Martin Dawson at The Rockefeller Hospital confirmed each of Griffith’s reported findings. Even before Griffith’s publication, Fred Neufeld, of Germany’s Robert Koch Institute – who had visited Griffith’s laboratory and had been told of Griffith’s findings – had confirmed them as well, Neufeld merely awaiting publication of Griffith’s findings before publishing confirmation. Over the following years, Avery’s illness, Grave’s disease, kept him much out of his laboratory as other researchers in it experimented to determine, largely by process of elimination, which constituent was the transforming factor.

 

Microbiologists endeavored during the 1930s to dispel the monomorphist tenet, prevailing as institutional dogma, largely prevailing into the 21st century.

 

Last days of Griffith and Colleague

 

The first Griffith Memorial Lecture indicates that Fred Griffith died on the night of 17 April 1941 – though the fourth lecture indicates that he died in his apartment in February 1941 – alongside friend and colleague William M. Scott amid an air raid during World War II’s London Blitz. A few weeks earlier Scott had become director of the laboratory, which, with the outbreak of war, had become Emergency Public Health Laboratory Service. Both dated 3 May 1941, his obituary in The Lancet mentions the historical discovery briefly, and his obituary in British Medical Journal fails to mention it.

 

Avery et al then Watson & Crick

 

In 1944 identification of the transforming factor was published in the Journal of Experimental Medicine by Avery, Colin MacLeod, and Maclyn McCarty of The Rockefeller Hospital. This identification departed from the prevailing belief that the protein content of chromosomes probably was the anatomical structure of genes, although it would take another decade – till Watson and Crick’s 1953 paper in Nature indicating DNA’s molecular structure suggesting how a molecule as seemingly simple as DNA could encode the structure of proteins – for the interpretation of DNA as genes to become widely accepted.

 

Applications

 

Biologists made little more than speculation of Griffith’s report of transformation until genetics research in 1951. In 1950 the U.S. Army began testing bacterial biowarfare on unwitting American civilians, and perhaps in Korea during the Korean War (though the officially trained U.S. policy was plausible denial.) Griffith’s report was virtually ignored by clinicians, and by the medical sector as a whole. Leaders of American industry, biomedicine, medical education, and prestigious medical journals – Journal of the American Medical Association and New England Journal of Medicine – continued to espouse population control and negative eugenics.

 

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Fred Griffith in 1936 with his pet terrier

 

 

Griffith‘s Further Work and Legacy

 

Bacteriology

 

In 1931 Fred Griffith coauthored a paper on acute tonsillitis – its sequelae, epidemiology, and bacteriology. In 1934 Griffith reported voluminous findings on the serological typing of Streptococcus pyogenes. More casually as well as medically called simply streptococcus, S pyogenes is implicated in conditions ranging from the usually minor strep throat, to the sometimes fatal scarlet fever, to the often fatal puerperal fever, to the usually fatal streptococcal sepsis. Streptococci infection was a frequent coinfection complicating recovery from lobar pneumonia by pneumococci infection.

 

In 1944 this “transforming principle“ was identified as being genetic by Oswald Avery, Colin MacLeod, and Maclyn McCarty. They isolated DNA from a virulent strain of S. pneumoniae and using just this DNA were able to make a harmless strain virulent. They called this uptake and incorporation of DNA by bacteria “transformation“ (See Avery-MacLeod-McCarty experiment). The results of Avery et al.’s experiments were at first skeptically received by the scientific community and it was not until the development of genetic markers and the discovery of other methods of genetic transfer (conjugation in 1947 and transduction in 1953) by Joshua Lederberg that Avery’s experiments were accepted.

 

By 1967 pneumococcal transformation had been evidenced to occur in vivo naturally, and it was shown that treatment with streptomycin during dual infection by two pneumococcal strains could increase transformation – and increase virulence – while for the first time pneumococcal transformation was shown to indeed occur in the respiratory tract. In 1969 it was shown in vivo that, during drug treatment of a host, pneumococci could acquire genes from antibiotic-resistant streptococci, already in the host, and thereby the pneumococci could newly attain resistance to erythromycin.

 

It was originally thought that Escherichia coli, a commonly used laboratory organism, was refractory to transformation. However, in 1970, Morton Mandel and Akiko Higa showed that E. coli may be induced to take up DNA from bacteriophage ? without the use of helper phage after treatment with calcium chloride solution.

 

Two years later in 1972, Stanley Cohen, Annie Chang and Leslie Hsu showed that CaCl 2 treatment is also effective for transformation of plasmid DNA. The method of transformation by Mandel and Higa was later improved upon by Douglas Hanahan. The discovery of artificially induced competence in E. coli created an efficient and convenient procedure for transforming bacteria which allows for simpler molecular cloning methods in biotechnology and research, and it is now a routinely used laboratory procedure.

 

Transformation using electroporation was developed in the late 1980s, increasing the efficiency of in-vitro transformation and increasing the number of bacterial strains that could be transformed. Transformation of animal and plant cells was also investigated with the first transgenic mouse being created by injecting a gene for a rat growth hormone into a mouse embryo in 1982. In 1907 a bacterium that caused plant tumors, Agrobacterium tumefaciens, was discovered and in the early 1970s the tumor inducing agent was found to be a DNA plasmid called the Ti plasmid. By removing the genes in the plasmid that caused the tumor and adding in novel genes researchers were able to infect plants with A. tumefaciens and let the bacteria insert their chosen DNA into the genomes of the plants. Not all plant cells are susceptible to infection by A. tumefaciens so other methods were developed including electroporation and micro-injection. Particle bombardment was made possible with the invention of the Biolistic Particle Delivery System (gene gun) by John Sanford in the 1980s.

 

Note: Griffiths’ discovery of transformation should not be confused with an unrelated process called malignant transformation which occurs in the progression of cancer.

 

In molecular biology, transformation is genetic alteration of a cell resulting from the direct uptake, incorporation and expression of exogenous genetic material (exogenous DNA) from its surroundings and taken up through the cell membrane(s). Transformation occurs naturally in some species of bacteria, but it can also be effected by artificial means in other cells. For transformation to happen, bacteria must be in a state of competence, which might occur as a time-limited response to environmental conditions such as starvation and cell density.

 

Transformation is one of three processes by which exogenous genetic material may be introduced into a bacterial cell, the other two being conjugation (transfer of genetic material between two bacterial cells in direct contact) and transduction (injection of foreign DNA by a bacteriophage virus into the host bacterium).

 

“Transformation“ may also be used to describe the insertion of new genetic material into nonbacterial cells, including animal and plant cells; however, because “transformation“ has a special meaning in relation to animal cells, indicating progression to a cancerous state, the term should be avoided for animal cells when describing introduction of exogenous genetic material. Introduction of foreign DNA into eukaryotic cells is often called transfection.

Lifestyle Intervention Improves Student’s Health, Social Skills, Grades

 

According to a study published online the September issue of the American Journal of Preventive Medicine has shown that a teacher-delivered intervention program promoting healthy lifestyles improved health behaviors, social skills, severe depression, and academic performance in high school adolescents. According to the authors, routine integration of such programs into health education curricula in high school settings may be an effective way to prevent high-risk teen populations from becoming overweight or obese, and could lead to improved physical health, psychosocial skills, and academic outcomes, according to the study.

 

The study was supported by the National Institute of Nursing Research (NINR), part of the National Institutes of Health and is one of the first studies to report multiple immediate improvements that were sustained over time using a teacher-delivered, cognitive-behavioral skills-building intervention program incorporated into a high school health education class. Cognitive-behavioral skills training teaches coping techniques, social functioning skills, and problem solving skills.

 

The randomized controlled trial examined the short- and long-term effects of the COPE (Creating Opportunities for Personal Empowerment) Healthy Lifestyles (TEEN) Thinking, Emotions, Exercise, Nutrition Program. The COPE TEEN program is an intervention targeting obesity, social skills, and mental health.

 

The study measured healthy lifestyle behaviors, body mass index (BMI), depressive symptoms, social skills, and the academic performance of 779 culturally diverse 14- to 16-year-old high school students, randomized to receive the COPE TEEN program or an attention control program. At the end of the program, COPE TEEN participants had significantly higher levels of physical activity, as measured by daily pedometer steps (an average of 13,861 steps per day compared to an average of 9,619 steps per day), and had a significantly lower mean BMI than the control group.

 

COPE TEEN adolescents also scored higher averages on a social skills scale measuring cooperation, assertion, and academic competence, and earned higher grades in the health course in which the intervention was given. They also reported significantly lower levels of alcohol use than teens not receiving the intervention (13% vs. 20%, respectively). Students with high depression scores prior to the intervention showed significantly lower depression scores that dropped from severe depressive symptoms into the normal range following COPE compared to similar students in the control group.

 

The COPE TEEN intervention program consisted of a 15-session education and cognitive-behavioral skills-building program taught by teachers once-a-week in a required health class. Each session consisted of 15 to 20 minutes of physical activity (e.g., walking, dancing, and kick boxing movements). The pedometers reinforced the physical activity component of the COPE program; students were asked to increase their step counts each week and to track their daily steps.

 

Six months after completing the intervention program, COPE teens retained a significantly lower BMI, and were less likely to have moved from the healthy weight category to an overweight or obese category relative to control group participants. For the COPE teens, 143 teens remained in the healthy weight category at six months, only four moved into the overweight category and none of the students progressed to the obese category. In the control group, 187 remained in the healthy weight category while 15 progressed to the overweight category; and three moved into the obese category.

 

Overall, the study results suggest that combining health education with cognitive-behavioral skills-building may be an effective way to prevent and treat overweight and obesity in teens.

 

According to the authors, further research is needed to continue to evaluate the effectiveness of the COPE program on a wider scale, including other groups of high-risk teens and an adapted version for middle-school children. In addition, the authors added that this study shows that the intervention can be a promising approach for promoting healthy lifestyles, improving psychosocial health and enhancing academic outcomes in a setting where teens spend a significant amount of time — in the classroom — and by teachers, who have been shown to be able to sustain longer-term, positive outcomes.“

Risk Factors Associated with Hypertrophic Cardiomyopathy (HCM) in Children

 

Hypertrophic cardiomyopathy, a type of pediatric cardiomyopathy (diseases of the heart muscle) with varied causes and outcomes, is characterized by increased thickness (hypertrophy) of the heart wall. HCM is rare, with fewer than one out of 100,000 children (ages birth to 18 years old) diagnosed annually in the United States. The condition is more frequently diagnosed in infants (under the age of one year), with 2 to 3 out of every 100,000 identified each year.

 

According to a study published online in The Lancet (3 September 2013), a long-term study of children with HCM found that the risk of death or need for immediate listing for heart transplantation was greatest for those who developed this disease as infants with congestive heart failure and for children who also had selective inborn errors of metabolism, a group of rare genetic disorders in which one or more of the body’s key metabolic processes are disrupted. Impressively, the authors spent 19 years amassing data on more than 1,000 affected children at 98 pediatric cardiology centers in the U.S. and Canada through the NHLBI-funded Pediatric Cardiomyopathy Registry.

 

Results showed that children with HCM caused by inborn errors of metabolism had the lowest rate of transplant-free survival within two years after diagnosis (43%). At two years after diagnosis, the rate of transplant-free survival was 55% for children with a mixed version of the disease that included thickening of the heart walls and enlargement and weakening of the heart, and 62% for those with a restrictive form of the disease characterized by both a thickening and hardening of the heart walls. Children diagnosed after age one year with hypertrophic cardiomyopathy of unknown cause had the most favorable outcome, a 97% rate of transplant-free survival.

 

Infants and children who had two or more of the following risk factors at HCM diagnosis (depending on the cause of HCM) — lower weight or body size, female gender, diagnosis during infancy, congestive heart failure, and abnormal heart function — had an increased risk of poor outcomes (death or need for immediate heart transplantation).

 

According to the authors, these findings are expected to assist clinicians in identifying which children are likely to have the worst outcomes (death or need for immediate heart transplantation) within two years of diagnosis, thereby enabling medical teams, genetic counselors, and family planners to jointly and quickly determine the best treatment approach.

 

SUPPLEMENTAL INFORMATION:

 

What is cardiomyopathy?

What is heart failure?

What is sudden cardiac arrest?

What is coronary heart disease?

Conquering cardiovascular disease

 

Diagram of a normal heart (left) and a heart with hypertrophic (increased thickness) cardiomyopathy (right).Image credit the American Heart Association.

TARGET HEALTH excels in Regulatory Affairs. Each week we highlight new information in this challenging area

 

Determining Whether Human Research Studies Can Be Conducted Without an IND

 

 

FDA has announced the availability of a guidance for clinical investigators, sponsors, and institutional review boards (IRBs) entitled “Investigational New Drug Applications (INDs) – Determining Whether Human Research Studies Can Be Conducted Without an IND.“ The guidance is intended to assist clinical investigators, sponsors, sponsor-investigators, and IRBs in determining whether human research studies must be conducted under an IND. The guidance describes the basic criteria for determining when an IND is required, describes specific situations in which an IND is not required, and addresses a range of issues that, in FDA’s experience, have been the source of confusion or misperceptions about the application of the IND regulations.

 

There have been many inquiries to FDA to FDA on the following:

 

1. Clinical investigations using marketed drugs

2. Bioequivalence/bioavailability studies

3. Studies using radiolabeled or cold isotopes

4. Studies using dietary supplements or foods

5. Studies using endogenous compounds

6. Pathogenesis studies using modified organisms

7. Studies using wild-type organisms in challenge models

8. Studies that do not have a commercial purpose

 

In terms of drug, an IND is not required if:

 

1. The drug product is lawfully marketed in the United States.

2. The investigation is not intended to be reported to FDA as a well-controlled study in support of a new indication and there is no intent to use it to support any other significant change in the labeling of the drug.

3. In the case of a prescription drug, the investigation is not intended to support a significant change in the advertising for the drug.

4. The investigation does not involve a route of administration, dose, patient population, or other factor that significantly increases the risk (or decreases the acceptability of the risk) associated with the use of the drug product (21 CFR 312.2(b)(1)(iii)).

5. The investigation is conducted in compliance with the requirements for review by an IRB (21 CFR part 56) and with the requirements for informed consent (21 CFR part 50).

6. The investigation is conducted in compliance with the requirements of ? 312.7 (i.e., the investigation is not intended to promote or commercialize the drug product).

Zucchini Parmesan Sticks with Marinara Sauce

 

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Call me a late bloomer, but I just discovered how to make fried zucchini, a much lower calorie dish. — BAKING — That’s right, just tweaking a little and baking instead of deep frying, puts this delicious comfort food right into our calorie conscious eating habits. Not only is this recipe healthy and yummy. It’s also very easy and quick to put together. And, now is the time when home-grown and/or local zucchini is plentiful; so go out and bring a few home.

 

Ingredients

Olive oil spray
4 to 6 fresh zucchini
2 to 4 egg whites
2 to 4 teaspoons of water
1 cup grated parmesan cheese
1 cup Panko crumbs
Pinch sea salt
Pinch black pepper
4 cups marinara sauce, or more to your taste

Directions

Prepare your own marinara sauce ahead of time, or use low sodium marinara from your store. Also, grate ahead of time, fresh parmesan for this recipe.

 

1. Heat oven to 450 degrees.

2. Use two non-stick baking sheets or with one spray (only), coat two baking sheets lightly with olive oil.

3. Clean zucchini and keep skin on.

4. Slice zucchini in half and then into sticks about ? wide. (see photo)

5. If the zucchini feel especially wet, spread them on a paper towel while you prepare the other ingredients.

6. In a small bowl, lightly beat first egg white with 1 teaspoon water to loosen it.

7. In another bowl, combine cheese, Panko crumbs, salt and pepper.

8. Dip each zucchini stick in the egg white, and be sure to cover the stick with the egg white. Let any excess egg white, run off. Then dip the sticks in the Panko/parmesan mixture.

9. Arrange in single layer on baking sheet. If additional egg white is needed, prepare it the same way, with 1 teaspoon of water for each egg white.

10. If additional crumb mixture is needed, make a few spoonfuls at a time, mixing equal amounts of Panko and Parmesan.

11. Bake the zucchini sticks until golden brown and crisp, about 25 to 30 minutes. After 12 minutes in the oven, turn the sticks, so they brown evenly. Feel free to stir them around, to brown evenly, before or after the 12 minutes. And check on them, to be sure they don’t burn. Ovens are different, you know your own oven, so check these sticks, accordingly, and remove them from the oven only when they’re golden brown all over.

 

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Coming Out of the Oven

 

 

1. Remove to cool slightly and serve while warm with marinara sauce.

2. Heat up the marinara sauce, if it’s cooled down.

 

Try to eat right away. These zucchini sticks are at their best right out of the oven. However, once when I made a whole bunch and there were some left-over, they were wonderful the next day after being warmed up in toaster oven or microwave.

 

These baked zucchini sticks are perfect as an appetizer to nibble on with your favorite wine (red or white) or beer. Or serve them as the veggie dish to accompany some fresh light flaky moist, poached or baked white fish like halibut or sole or tilapia or red snapper. The recipe, above is for two to four people.

 

You can also make a lot so there’s enough for a veggie lunch the next day. We’re going through a craze for these little sticks and have already had them three or four times since we’ve been back from our Santa Fe vacation.

 

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Enjoy!

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