Regulatory Affairs at Target Health

The Regulatory Department at Target Health Inc, headed by Glen Park, PharmD., includes Dr. Jules Mitchel, Mary Shatzoff, Fredy Varela, Daisy Sun, and Carlos Figueroa. Our regulatory group represents over 30 companies at FDA, represents several companies in Canada, prepares about 3 new INDs each year and meets with FDA about 10 times a year. To their credit is 1 approved NDA, 1 approved PMA, eight (8) Orphan Drug Designations (with two in review), and nine cleared 510(k) devices. The team is currently preparing an eCTD for an orphan disease where they performed all the regulatory strategic planning. The Regulatory team also collaborated with one of our clients on their NDA for another orphan disease. They are also preparing Module 1 for an eCTD for a drug which was recently approved in Europe, where Target Health also prepared major parts of the Module 5. Target e*CRF® has been used in 17 unique regulatory approvals world-wide (4 NDAs, 1 BLA, 10 PMAs, 1 MAA and 1 510(k). Three of the NDAs were also approved in Canada and Europe.

For more information about Target Health and any of our software tools for paperless clinical trials, please contact Dr. Jules T. Mitchel (212-681-2100 ext 0) or Ms. Joyce Hays. Target Health’s 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.

Stem Cells Embed In Sutures Enhance Healing

Johns Hopkins biomedical engineering students have demonstrated a practical way to embed a person’s own 1) ___ stem cells in the surgical thread that doctors use to repair serious orthopedic injuries, such as ruptured tendons. The goal is to enhance healing and reduce the likelihood of re-injury without changing the surgical procedure itself. The project team, which included 10 undergraduates, won first place in the Design Day 2009 competition conducted by the university’s Department of Biomedical Engineering. In collaboration with 2) ___ physicians, the students have begun testing the stem cell-bearing sutures in an animal 3) ___, paving the way for possible human trials within about five years. This technology has great promise for the treatment of debilitating tendon, ligament and muscle injuries, often sports-related, that affect thousands of young and middle-aged adults annually. Using sutures that carry 4) ___ cells to the injury site would not change the way surgeons repair the injury, but the stem cells should, significantly speed up and improve the healing process. And because the stem cells will come from the 5) ___, there should be no rejection problems. The corporate sponsor enlisted the student team to assemble and test a prototype to demonstrate that the concept was sound. The undergraduates performed this work during the yearlong Design Team course, required by the school’s Biomedical Engineering Department. The team located a machine that could weave surgical thread in a way that would ensure the most effective delivery and long-term survival of the stem cells. The team conducted some aspects of the animal testing, although orthopedic physicians performed the surgical procedures. As envisioned by the sponsoring company and the students, a doctor would withdraw bone marrow containing stem cells from a patient’s 6) ___ while the patient was under anesthesia. The stem cells would then be embedded in the novel suture through a quick and easily performed proprietary process. The surgeon would then stitch together the ruptured Achilles tendon or other injury in the conventional manner but using the sutures 7) ___ with stem cells. At the site of the injury, the stem cells are expected to reduce inflammation and release growth factor proteins that speed up the healing, enhancing the prospects for a full recovery and reducing the likelihood of re-injury. The team’s preliminary experiments in an animal model have yielded promising results, indicating that the stem cells attached to the 8) ___ can survive the surgical process and retain the ability to turn into replacement tissue, such as tendon or cartilage. Researching the business opportunity, the students found that about 46,000 people in the US undergo Achilles tendon repair surgery every year. The operation and subsequent therapy costs are about $40,000 per case. After surgery, the recovery process can take up to a year. In about 20% of the cases, the surgery fails, and another operation is needed. Anything that can be done to speed up the 9) ___ and lower the failure rate and the additional medical costs could make a big difference. The student team has demonstrated an amazing amount of initiative and leadership in all aspects of this project, including actually producing the suture and designing the ensuing mechanical, cell-based and animal trials. The students have probably cut at least a year off of the development time of this technology, and they are definitely advancing the 10) ___ in this emerging area.

ANSWERS: 1) adult; 2) orthopedic; 3) model; 4) stem; 5) patient; 6) hip; 7) embedded; 8) sutures; 9) healing; 10) science

St. John’s Wort: (Hypericum perforatum)

St. John’s Wort (Hypericum perforatum) is regarded as a medicinal herb, wildflower, and weed. Historically, it has been used as a curative herb for centuries. Because its’ first summer flowers appear near or even on the summer solstice, it was always an icon of sun worshippers and used in solstice rituals by the Druids, the Celts and the Saxons. For centuries the Romans burned it in bonfires as part of their celebration of Midsummer’s Day. St. John’s wort was used in early pre-Christian religious practices in England, and it has many legends written about it. Because of its bright yellow color, it was often associated with the sun and was often used for purposes of divination–for every situation from longevity to test one’s chances for matrimony. To predict their chances for marital bliss, young girls were in the habit of plucking a sprig of flowers – if the flowers were fresh in the morning, their chances were good, if wilted, a dismal outcome was predicted. The renowned Greek herbalists of the 1st century CE – Pliny, Discorides and Hippocrates – all used this herb, while the ancient Greek scholar, Galen, described it as ‘the antidote to intestinal worms.’ Hypericum was recommended by Hippocrates for “nervous unrest.” It has a 2400-year history of folk use for anxiety; sleep disturbances, and worry. Galen and Dioscorides recommended it as a diuretic, wound healing herb, and a treatment for menstrual disorders. The herb was administered as a remedy by the Roman military doctor Proscurides as early as the 1st century AD. Dioscorides claimed that it “expels many cholerick excrement, but it must be given continuously, until they be cured, and being smeared on it is good for ambusta (burns).” Pliny said that it should be taken in wine against poisonous reptiles. The faint black marks on the leaves of this herb were said to be a symbol of the beheading of St. John the Baptist at the cruel insistence of Herod’s daughter, Salome. If the blossoms are put in oil and left to infuse in the sun, the oil gradually becomes a rich red. Traditionally, this was known as St. John’s Blood. Today, modern American herbalists still use St. John’s wort for many of the same conditions for which it has been recommended throughout the ages and many commercial preparations are available either as an oil or a standardized liquid or powdered extract. In Europe, these preparations are commonly prescribed by medical doctors for burns, ulcers and nervous disorders, especially mild depression. Scientific studies have been performed in the laboratory and clinic to support these uses, some of which follow the ancient applications detailed above. With a documented history of continuous use for over 2,000, St. John’s wort may find new applications and wider acceptance into the 21st century.

GENETICS

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Genetic Variants Linked To Blood Pressure In African-Americans

Hypertension, or chronic high blood pressure, underlies an array of life-threatening conditions, including heart disease, stroke and kidney disease. Diet, physical activity and obesity all contribute to risk of hypertension, but genetics may also play an important role. About one-third of U.S. adults suffer from hypertension. The burden is considerably greater in the African-American community, in which the condition affects 39% of men and 43% of women. According to an article published in the July 17 online issue of PLoS Genetics, a relatively new research approach, called a genome-wide association study, focused on blood pressure and hypertension in an African-American population. In a genome-wide association study, researchers identify strategically selected markers of genetic variation. If disease status differs for individuals with certain genetic variants, this indicates that something in that chromosomal neighborhood likely influences the disease. Variants detected using this approach can accurately point to the region of the genome involved, but may not themselves directly influence the trait. For the study, DNA samples were analyzed from 1,017 participants in the Howard University Family Study, a multigenerational study of families from the Washington, D.C., metropolitan area who identified themselves as African-American. Half of the volunteers had hypertension and half did not. To see if there were any genetic differences between the two groups, the volunteers’ DNA was scanned to analyze more than 800,000 genetic markers called single-nucleotide polymorphisms (SNPs). The study found five genetic variants significantly more often in people with hypertension than in those without the condition. The variants were associated with high systolic blood pressure, but not with diastolic blood pressure or combined systolic/diastolic blood pressure. Blood pressure is measured in millimeters of mercury (mm Hg), and expressed with two numbers; for example, 120/80 mm Hg. The first number (systolic pressure) is the pressure when the heart beats while pumping blood. The second number (diastolic pressure) is the pressure in large arteries when the heart is at rest between beats. In May, two major international studies used the genome-wide association approach to identify 13 genetic variants associated with blood pressure and hypertension in people with primarily European and South Asian ancestry.  While each variant was associated with only a slight increase in blood pressure, that work found that the more variants an individual had, the greater his or her risk of hypertension. Two genes identified by one of those studies were also associated with blood pressure in the new study. In the current pioneering study of African-Americans, it found that all of the five genetic variants associated with blood pressure were located in or near genes that code for proteins thought to be biologically important in hypertension and blood pressure. Previous research had implicated two of those genes in blood pressure regulation, and additional analyses revealed that all of the variants are likely involved in biological pathways and networks related to blood pressure and hypertension. An existing class of anti-hypertension drugs, called calcium channel blockers, already targets one of the genes, CACNA1H. However, the additional genes may point to new avenues for treatment and prevention. To follow up and expand upon their findings in African-Americans, the study scanned DNA from 980 West Africans with and without hypertension. The work confirmed that some of the genetic variants detected in African-Americans were also associated with blood pressure in West Africans.

Diet and Lifestyle Risk Factors Associated With Incident Hypertension in Women

Hypertension is an important preventable risk factor for death among women. While several modifiable risk factors have been identified, their combined risk and distribution in the population have not been assessed. As a result, a study published in the Journal of the American Medical Association (2009;302:401-411) to estimate the hypothetical fraction of hypertension incidence associated with dietary and lifestyle factors in women. The investigation was a prospective cohort study of 83,882 adult women aged 27 to 44 years in the second Nurses’ Health Study who did not have hypertension, cardiovascular disease, diabetes, or cancer in 1991, and who had normal reported blood pressure (defined as systolic blood pressure of 120 mm Hg and diastolic blood pressure of 80 mm Hg), with follow-up for incident hypertension for 14 years through 2005. Six modifiable lifestyle and dietary factors for hypertension were identified. The 6 low-risk factors for hypertension were a body mass index (BMI) of less than 25, a daily mean of 30 minutes of vigorous exercise, a high score on the Dietary Approaches to Stop Hypertension (DASH) diet based on responses to a food frequency questionnaire, modest alcohol intake up to 10 g/day, use of nonnarcotic analgesics less than once per week, and intake of 400 ?g/d or more of supplemental folic acid. Results were analyzed by evaluating the association between combinations of 3 (normal BMI, daily vigorous exercise, and DASH-style diet), 4 (3 low-risk factors plus modest alcohol intake), 5 (4 low-risk factors plus avoidance of nonnarcotic analgesics), and 6 (folic acid supplementation 400 ?g/d) low-risk factors and the risk of developing hypertension. The main outcome measure was the adjusted hazard ratios for incident self-reported hypertension and population attributable risks (PARs). During the study, a total of 12,319 incident cases of hypertension were reported. All 6 modifiable risk factors were independently associated with the risk of developing hypertension during follow-up after also adjusting for age, race, family history of hypertension, smoking status, and use of oral contraceptives. For women who had all 6 low-risk factors (0.3% of the population), the hazard ratio for incident hypertension was 0.22; the hypothetical PAR was 78% for women who lacked these low-risk factors. Body mass index alone was the most powerful predictor of hypertension, with a BMI of 25 or greater having an adjusted PAR of 40%  compared with a BMI of less than 25. According to the authors, adherence to low-risk dietary and lifestyle factors was associated with a significantly lower incidence of self-reported hypertension, and adopting low-risk dietary and lifestyle factors has the potential to prevent a large proportion of new-onset hypertension occurring among young women.

A Child’s IQ Can Be Affected By Mother’s Exposure To Urban Air Pollutants

According to an article published in Pediatrics (August 2009; Volume124), a mother’s exposure to urban air pollutants known as polycyclic aromatic hydrocarbons (PAHs) can adversely affect a child’s intelligence quotient or IQ. PAHs are chemicals released into the air from the burning of coal, diesel, oil and gas, or other organic substances such as tobacco. In urban areas motor vehicles are a major source of PAHs. The study, funded by the National Institute of Environmental Health Sciences (NIEHS), the U.S. Environmental Protection Agency and several private foundations, found that children exposed to high levels of PAHs in New York City had full scale and verbal IQ scores that were 4.31 and 4.67 points lower than those of less exposed children. High PAH levels were defined as above the median of 2.26ng/m3. A difference of four points, which was the average seen in this study, could be educationally meaningful in terms of school success. The study was conducted by scientists from the Columbia University Center for Children’s Environmental Health, and included children who were born to non-smoking black and Dominican-American women age 18 to 35 who resided in Washington Heights, Harlem or the South Bronx in New York. The children were followed from utero to 5 years of age. The mothers wore personal air monitors during pregnancy to measure exposure to PAHs. At 5 years of age, 249 children were given an intelligence test known as the Wechsler Preschool and Primary Scale of the Intelligence, which provides verbal, performance and full-scale IQ scores. The test is regarded as a well validated, reliable and sensitive instrument for assessing intelligence. The researchers developed statistical models to calculate the associations between prenatal PAH exposure and IQ, and accounted for other factors such as second-hand smoke exposure, lead, mother’s education and the quality of the home caretaking environment. Study participants exposed to air pollution levels below the average were designated as having low exposure, while those exposed to pollution levels above the median were identified as high exposure.

TARGET HEALTH excels in Regulatory Affairs and works closely with many of its clients performing all FDA submissions. TARGET HEALTH receives daily updates of new developments at FDA. Each week, highlights of what is going on at FDA are shared to assure that new information is expeditiously made available.

FDA and Public Health Experts Warn About Electronic Cigarettes

Electronic cigarettes, also called “e-cigarettes,” are battery-operated devices that generally contain cartridges filled with nicotine, flavor and other chemicals. The electronic cigarette turns nicotine, which is highly addictive, and other chemicals into a vapor that is inhaled by the user. These products are marketed and sold to young people and are readily available online and in shopping malls. In addition, these products do not contain any health warnings comparable to FDA-approved nicotine replacement products or conventional cigarettes. They are also available in different flavors, such as chocolate and mint, which may appeal to young people. The FDA has announced that a laboratory analysis of electronic cigarette samples has found that they contain carcinogens and toxic chemicals such as diethylene glycol, an ingredient used in antifreeze. Public health experts have previously expressed concern that electronic cigarettes could increase nicotine addiction and tobacco use in young people. Because these products have not been submitted to the FDA for evaluation or approval, at this time the agency has no way of knowing, except for the limited testing it has performed, the levels of nicotine or the amounts or kinds of other chemicals that the various brands of these products deliver to the user. The FDA’s Division of Pharmaceutical Analysis analyzed the ingredients in a small sample of cartridges from two leading brands of electronic cigarettes. In one sample, the FDA’s analyses detected diethylene glycol, a chemical used in antifreeze that is toxic to humans, and in several other samples, the FDA analyses detected carcinogens, including nitrosamines. These tests indicate that these products contained detectable levels of known carcinogens and toxic chemicals to which users could potentially be exposed. The FDA has been examining and detaining shipments of e-cigarettes at the border and the products it has examined thus far meet the definition of a combination drug-device product under the Federal Food, Drug, and Cosmetic Act. The FDA has been challenged regarding its jurisdiction over certain e-cigarettes in a case currently pending in federal district court. The agency is also planning additional activities to address its concerns about these products.

For more information about our expertise in Regulatory Affairs, please contact Dr. Jules T. Mitchel or Dr. Glen Park.

Target Health (www.targethealth.com) is a full service eCRO with full-time staff dedicated to all aspects of drug and device development. Areas of expertise include Regulatory Affairs, comprising, but not limited to, IND (eCTD), IDE, NDA (eCTD), BLA (eCTD), PMA (eCopy) and 510(k) submissions, Management of Clinical Trials, Biostatistics, Data Management, EDC utilizing Target e*CRF®, Project Management, and Medical Writing. Target Health has developed a full suite of eClinical Trial software including 1) Target e*CRF® (EDC plus randomization and batch edit checks), 2) Target e*CTMSTM, 3) Target Document®, 4) Target Encoder®, 5) Target Newsletter®, 6) Target e*CTRTM (electronic medical record for clinical trials). Target Health ‘s Pharmaceutical Advisory Dream Team assists companies in strategic planning from Discovery to Market Launch. Let us help you on your next project.