Innovation at Target Health – DIA Boston – Booth 226

 

To our dedicated and loyal readers who will be in Boston at the annual meeting of the DIA, please visit us at Booth 226. Appointments are appreciated but clearly not required. Those representing Target Health will be Warren Pearlson, Dean Gittleman, Judith Schloss Markowitz, Caryn Trbovic, Tony Pinto, Neil Lassalle and Jules Mitchel.

 

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.

Birth Control

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Birth control, also known as contraception and fertility control, are methods or devices used to prevent 1) ___. Planning and provision of birth control is called family planning. The use of male or female condoms, can also help prevent transmission of STD infections. Contraceptive use in developing countries has cut the number of maternal 2) ___ by 44% (about 270,000 deaths averted in 2008) but could prevent 73% if the full demand for birth control were met. Because teenage pregnancies are at greater risk of poor outcomes such as preterm birth, low birth weight and infant death, some authors suggest adolescents need comprehensive education and access to reproductive health services, including contraception. By lengthening the time between pregnancies, birth control can also improve adult women’s delivery outcomes and the survival of their 3) ___.

 

Effective birth control methods include barriers such as condoms, diaphragms, and the contraceptive sponge; hormonal contraception including oral pills, patches, vaginal rings, and injectable contraceptives; and IUDs or 4) ___ ___. Emergency contraception can prevent pregnancy after unprotected relations. Long-acting reversible contraception, such as implants, IUDs, or vaginal rings, is recommended to reduce teenage pregnancy. Sterilization by means such as vasectomy and tubal ligation is permanent contraception. Some people regard sexual abstinence as birth control, but abstinence-only education often increases 5) ___ pregnancies when offered without contraceptive education.

 

Birth control methods have been used since ancient times but effective and safe methods only became available in the 6) ___ century. Some cultures deliberately limit access to contraception because they consider it to be morally or politically undesirable. About 222 million women who want to avoid pregnancy in developing countries are not using a modern contraception method. Birth control increases economic growth because of fewer dependent children, more women participating in the workforce, and less consumption of scarce resources. Women’s earnings, assets, body mass index, and their children’s schooling and all substantially improve with greater access to 7) ___.  In addition, the diminution of STDs like HIV and herpes, has a huge, effect on a society, when condoms are used.  It goes without saying, that the elimination of suffering, and death of parents and children, from terrible diseases, is priceless to families and to all of society.

 

 

Lactation

The lactational amenorrhea method, involves the use of a woman’s natural postpartum infertility which occurs after delivery and may be extended by breastfeeding. This usually requires the presence of no periods, exclusively breastfeeding the infant, and a child younger than six months. If breastfeeding is the infant’s only source of nutrition the World Health Organization states that it is 98% effective in the six months following delivery. Trials have found effectiveness rates between 92.5% and 100%. Effectiveness decreases to 93-96% at one year and 87% at two years. Feeding formula, pumping instead of nursing, the use of a pacifier, and feeding solids all reduce its effectiveness. In those who are exclusively breastfeeding about 10% begin having periods before three months and 20% before six months. In those who are not 8) ___ fertility may return four weeks after delivery.

 

ANSWERS: 1) pregnancy; 2) deaths; 3) children; 4) intrauterine devices; 5) teen; 6) 20th; 7) contraception; 8) breastfeeding

Birth Control

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Ancient silver coin from the Greek city, Cyrene, now modern-day Libya, depicting a stalk of silphium.

 

 

According to the oldest recorded information regarding birth control, a document that is nearly 4,000 years old – the Egyptian Kahun Gynecological Papyrus, which also happens to be the first known medical text – women used pessaries made out of crocodile dung (acidic) and honey (antibacterial) as a form of contraception. In addition to physically preventing sperm from fertilizing an egg, the acidic properties of the dung may have served as an effective spermicide. In India, elephant dung has been used in this same manner. Another method the text describes on top of the “crocodile dung” was the use of acacia gum, which does work as a spermicide. It can even be found in some spermicide products today.

 

The Egyptian Ebers Papyrus from 1550 BCE and the Kahun Papyrus from 1850 BCE have within them some of the earliest documented descriptions of birth control, the use of honey, acacia leaves and lint to block sperm. Ancient Egyptian drawings also show the use of condoms. The Book of Genesis references withdrawal, or coitus interruptus, as a method of contraception when Onan “spills his seed” (ejaculates) on the ground so as to not father a child with his deceased brother’s wife Tamar.

 

Dating back to ancient Greece and spanning a good 1,800 years of human history was the idea that drinking the water a blacksmith used to cool the materials he was working with would prevent pregnancy. Though it’s not really known why anyone believed this, the idea that the water contained lead is a strong possibility as even up through First World War, women were volunteering to work in factories with lead just so it would keep them sterile. The terrible downside was neurological problems, nausea, kidney failure, seizures, coma and death. In Ancient Greece, it is believed that silphium was used as birth control which due to its effectiveness and thus desirability was harvested into extinction.

 

In the fourth century BCE, Aristotle, was reportedly the first Greek writer to mention contraception. The philosopher recommended that women “anoint that part of the womb on which the seed falls” with olive oil in order to prevent pregnancy. His other top picks for spermicides included cedar oil, lead ointment, or frankincense oil. If the lips of the cervix were smooth, he noted, then conception would be difficult. The ancient Greeks also practiced what they hoped would be postcoital contraception by squatting and exerting pressure on the abdomen.

 

In medieval Europe any efforts to halt pregnancy were deemed immoral by the Catholic Church. It is believed that women of the time still used a number of birth control measures such coitus interruptus and the insertion of lily root and rue (and, in addition, infanticide after birth).

 

During the Middle Ages, a sausage maker came up with the idea of using the same animal intestines used for sausages, as condoms. This logical connection became the order of the day. One of the oldest known condoms is made from a pig intestine and even has a user manual that suggests soaking it in warm milk before use.

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Consider chastity belts an early attempt at abstinence-only education. These devices—more shackles than belt – first appeared in Europe in the 15th century. They were designed to keep women pure by making it physically impossible for them to have intercourse, making the inability to get pregnant an inevitable consequence. The belts, which featured small openings to allow for urination and defecation, were often made in only one size, so larger women were forced to endure the pain of a tight fit. The engraving shows a woman wearing a chastity belt. The chastity belt shown here has a padlock on the side.

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Condoms were first used in the 16th century as protection against syphilis (though there are earlier reports of ancient Egyptians using animal membranes as something of a proto-condom). Giacomo Girolamo Casanova (1725-1798) was among the first to use condoms (some made out of lambskin) to prevent pregnancy. The engraving above shows the Italian seducer blowing up a condom. The photo shows an early 19th-century contraceptive sheath made of animal gut and packaged in a paper envelope.

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In 1844, the American inventor Charles Goodyear (1800-1860) patented the vulcanization of rubber, which led to the mass production of condoms. This image from 1839 shows Goodyear demonstrating his new dry-heat rubber-vulcanization process, which prevented rubber from becoming sticky. Today, a wide variety of multicolored and multiflavored latex condoms are available to consumers.

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In 1873, Congress passed the Comstock Act, making it illegal to send contraceptive devices and information through the mail. The law was named after its chief advocate, the anti-obscenity crusader Anthony Comstock (pictured on left). More than 20 states passed similar prohibitions. Connecticut’s law was among the strictest: “Any person who will use any drug, medicinal article or instrument for the purpose of preventing conception shall be fined not less than fifty dollars or imprisoned not less than sixty days nor more than one year or be both fined and imprisoned.” That same year, Comstock and his supporters in the YMCA founded the New York Society for the Suppression of Vice, an institution to supervise public morality. The symbol of the society (pictured on right) advocated the burning of obscene books.

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As far back as ancient Egypt, women were using sponges as a method of preventing pregnancy. The sponge has its roots in early Egyptian civilization, and this photo depicts the variety of models available in the early 20th century. Those sponges were made of a variety of materials, and were sometimes drenched in lemon juice or vinegar to act as a spermicide. Today’s sponges (called, in fact, Today’s Sponge) are synthetic, and use a chemical spermicide.

 

In 1909, Richard Richter developed the first intrauterine device made from silkworm gut which was further developed and marketed in Germany by Ernst Grafenberg in the late 1920s.

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The Scottish-born Dr. Marie Stopes (1880-1958) was a leading advocate of birth control in the early 20th century. In 1918 Stopes wrote a guide to contraception called Wise Parenthood. In the face of opposition from the church, Stopes founded the Society for Constructive Birth Control and opened the first of her birth-control clinics in Holloway in North London in 1921. The image on the right shows Stopes working in the laboratory, where she helped to modify the contraceptive cap. The image on the left depicts a rubber cervical cap from around the 1920s.

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American activist Margaret Sanger (1879-1966) coined the phrase “birth control.” Born to an Irish-Catholic family, Sanger watched her mother, worn out after 18 pregnancies and 11 live births, die slowly. In a series of articles titled “What Every Girl Should Know” and in her newspaper, The Woman Rebel, Sanger (at left) strived to provide women with information about contraception. At neighborhood clinics, she provided women with controlled forms of birth control. Sanger is perhaps most well-known for founding the American Birth Control League, which eventually became Planned Parenthood, in 1921. At right: New York City police raid the Birth Control Research Bureau in New York City, ushering women into a patrol wagon in 1929. In 1931 historian and novelist H. G. Wells predicted that the movement Sanger started would, in 100 years, grow to be “the most influential of its time.”

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During the Great Depression, companies used the term “feminine hygiene” to market an array of products believed to have a contraceptive effect. One of the most popular of these was the cheap and dangerous “Lysol douche,” marketed as both a contraceptive and a cleansing agent. An ad for Lysol as hygiene product is shown, above. Later reports revealed that Lysol – surprise! – caused vaginal scalding. Another dangerous form of contraception from the 1930s was the stem pessary, an early version of the intrauterine device. These IUDs, pictured here, consisted of a rubber, metal, or glass stem connected to a cup or button to hold the stem upright and prevent it from becoming lost in the uterus.

 

The first formulations of birth-control pills, called Enovid, were submitted to the FDA for approval in 1957 as treatment for menstrual disorders or infertility. Coincidentally, a large number of American women developed menstrual disorders around this time. By 1959, more than half a million American women were taking Enovid. It wasn’t until three years later that the manufacturer presented the same oral contraceptive to the FDA to prevent pregnancy. By 1964, the pill had become the most popular form of birth control in the United States.

 

A Molecular Explanation for Age-Related Fertility Decline in Women

 

In general, a woman’s ability to conceive and maintain a pregnancy is linked to the number and health of her egg cells. Before a baby girl is born, her ovaries contain her lifetime supply of egg cells (known as primordial follicle oocytes) until they are more mature. As she enters her late 30s, the number of oocytes – and fertility – dips precipitously. By the time she reaches her early 50s, her original ovarian supply of about 1 million cells drops virtually to zero. Only a small proportion of oocytes — about 500 — are released via ovulation during the woman’s reproductive life. The remaining 99.9% are eliminated by the woman’s body, primarily through cellular suicide, a normal process that prevents the spread or inheritance of damaged cells.

 

Scientists supported by the National Institutes of Health have a new theory as to why a woman’s fertility declines after her mid-30s. They also suggest an approach that might help slow the process, enhancing and prolonging fertility. The study, published online in Science Translational Medicine (13 Feb 2013) showed that as women age, their egg cells become riddled with DNA damage and die off because their DNA repair systems wear out. Defects in one of the DNA repair genes — BRCA1 — have long been linked with breast cancer, and now also appear to cause early menopause.

 

The authors hypothesized that most aging oocytes self-destruct because they have accumulated a dangerous type of DNA damage called double-stranded breaks. According to the study, older oocytes have more of this sort of damage than do younger ones. The authors also found that older oocytes are less able to fix DNA breaks due to their dwindling supply of repair molecules.

 

Examining oocytes from mice, and from women 24 to 41 years old, the authors found that the activity of four DNA repair genes (BRCA1, MRE11, Rad51 and ATM) declined with age. When the research team experimentally turned off these genes in mouse oocytes, the cells had more DNA breaks and higher death rates than did oocytes with properly working repair systems. The team’s findings stemmed from their initial focus on BRCA1, a DNA repair gene that has been closely studied for nearly 20 years because defective versions of it dramatically increase a woman’s risk of breast cancer.

 

Using mice bred to lack the BRCA1 gene, it was confirmed that a healthy version of BRCA1 is vital to reproductive health. BRCA1-deficient mice were less fertile, had fewer oocytes, and had more double-stranded DNA breaks in their remaining oocytes than did normal mice.

 

Abnormal BRCA1 appears to cause the same problems in humans – the team’s studies suggest that if a woman’s oocytes contain mutant versions of BRCA1, she will exhaust her ovarian supply sooner than women whose oocytes carry the healthy version of BRCA1.

 

Together, these findings show that the ability of oocytes to repair double-stranded DNA breaks is closely linked with ovarian aging and, by extension, a woman’s fertility. This molecular-level understanding points to new reproductive therapies, including ways to bolster DNA repair systems in the ovaries might lead to treatments that can improve or prolong fertility.

Therapies for Active Rheumatoid Arthritis after Methotrexate Failure

 

Few blinded trials have compared conventional therapy consisting of a combination of disease-modifying antirheumatic drugs with biologic agents in patients with rheumatoid arthritis (RA) who have active disease despite treatment with methotrexate – a common scenario in the management of RA. As a result, a 48-week, double-blind, noninferiority clinical trial, published online in the New England Journal of Medicine (11 June 2013), randomly assigned 353 participants, with active RA despite methotrexate therapy, to a triple regimen of disease-modifying antirheumatic drugs (methotrexate, sulfasalazine, and hydroxychloroquine) or etanercept plus methotrexate. Patients who did not have an improvement at 24 weeks according to a prespecified threshold were switched in a blinded fashion to the other therapy. The primary outcome was improvement in the Disease Activity Score for 28-joint counts (DAS28, with scores ranging from 2 to 10 and higher scores indicating more disease activity) at week 48.

 

Results showed that both groups had significant improvement over the course of the first 24 weeks (P=0.001 for the comparison with baseline). A total of 27% of participants in each group required a switch in treatment at 24 weeks. Participants in both groups who switched therapies had improvement after switching (P<0.001), and the response after switching did not differ significantly between the two groups (P=0.08). The change between baseline and 48 weeks in the DAS28 was similar in the two groups (-2.1 with triple therapy and -2.3 with etanercept and methotrexate, P=0.26). Triple therapy was noninferior to etanercept and methotrexate, since the 95% upper confidence limit of 0.41 for the difference in change in DAS28 was below the margin for noninferiority of 0.6 (P=0.002). There were no significant between-group differences in secondary outcomes, including radiographic progression, pain, and health-related quality of life, or in major adverse events associated with the medications.

 

According to the authors, with respect to clinical benefit, triple therapy, with sulfasalazine and hydroxychloroquine added to methotrexate, was noninferior to etanercept plus methotrexate in patients with RA who had active disease despite methotrexate therapy.

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

 

 

FDA Approves Xgeva (Amgen) to Treat Giant Cell Tumor of the Bone

 

 

The FDA has expanded the approved use of Xgeva (denosumab) to treat adults and some adolescents with giant cell tumor of the bone (GCTB), a rare and usually non-cancerous tumor.

 

GCTB generally occurs in adults between the ages of 20 and 40 years. In most cases, GCTB does not spread to other parts of the body but destroys normal bone as it grows, causing pain, limited range of motion and bone fractures. Rarely, GCTB can transform into a cancerous tumor and spread to the lungs.

 

Xgeva is a monoclonal antibody that binds to RANKL, a protein essential for maintenance of healthy bone. RANKL is also present in GCTB. Xgeva is intended for patients whose GCTB cannot be surgically removed (unresectable) or when surgery is likely to result in severe morbidity, such as loss of limbs or joint removal. It should only be used in adolescents whose bones have matured.

 

The FDA reviewed Xgeva under its priority review program, which provides for an expedited review of drugs. Xgeva was granted orphan product designation because it is intended to treat a rare disease or condition. The safety and effectiveness of Xgeva for GCTB were established in two clinical trials that enrolled a total of 305 adult or adolescent patients. All patients had confirmed cases of GCTB that were recurrent, unresectable or where surgery would result in severe morbidity.

 

Of the 187 patients whose tumors could be measured, 47 patients had their tumors reduce in size after an average of three months. Over an average follow-up duration of 20 months, re-growth of GCTB occurred in three patients whose tumors originally became smaller during treatment.

 

Common side effects included joint pain (arthralgia), headache, nausea, fatigue, back pain and extremity pain. The most common serious side effects were osteonecrosis (areas of dead bone) of the jaw and osteomyelitis (inflammation or infection of the bone). Women of reproductive potential should use highly effective contraception while taking Xgeva because of potential fetal harm.

 

Xgeva was approved in 2010 to prevent fractures when cancer has spread to the bones. It is marketed by Amgen, based in Thousand Oaks, Calif.

Radish Cucumber Salad with Scallions, Dill and Sour Cream

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Ingredients

 

1) 1 English cucumber (keep skin on) or 3 Kirby cucumbers, or 3-4 mini seedless cucumbers (keep skin on)

2) 6-7 medium sized radishes, sliced thinly (1/8”), then halved

3) 3 scallions, white and green parts, chopped (discard rough green ends)

4) 1/4 cup fresh dill, chopped (or to your taste)

5) 4 Tablespoons sour cream (or to your taste)

6) 1/2 teaspoon salt (optional)

7) Pinch black pepper (or grind to your taste)

 

Directions

 

1) Wash all veggies and dry on paper towel.

2) Quarter the cucumbers lengthwise, then slice into 1/8-inch pieces.

3) Slice the radishes, thinly, no more than 1/8” thick

4) Place cucumbers, radishes, scallions and dill into a large bowl. Add the salt, pepper and toss well to combine. Add the sour cream and toss again. Serve immediately.

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Beautiful and fresh, from our local organic green grocer

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Chopped and ready to go

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With the addition of crumbled feta cheese – delicious

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With the addition of sliced red (new) potatoes – yummy

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With the addition of just a few carrot shavings – beautiful

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If you use arugula, prepare it first, then add the other veggies, seasoning and toss; then last toss with the sour cream

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With the addition of arugula (about 4 cups) – tasty with a little extra zip

 

 

Well, my dearest guinea pig husband came back from his Middle East business trip on Thursday, hungry and just in time to sample this delicious salad; which, btw, is easy to prepare.  On the first crunchy bite, his face lit up and I knew it was a success.  We both chewed on and he thought the radishes were a bit strong.  Luckily, I know him well and am usually prepared for many options when cooking for him.  “How ‘bout adding some crumbled feta”, I said, and did.  He was happy again.

 

We both liked it enough to have another variation on Friday; this time with thinly (but not so thin that they break up) sliced (about 1/8”) red new potatoes.  I handpicked tiny ones and used 8, with the red skins left on, of course.  Roasted them in the oven, then cooled, then sliced.  Cool in fridge to hasten the process, if you’re short on time.  You might want to add a little extra sour cream.  You can use your imagination and do your own variations on this wonderful salad or simply make the first version, which is so-o refreshing and cool on a warm summer evening.  Would certainly be good at any barbecue.  And, let me repeat – e a s y.

 

If you don’t mind the starch, the potato version turned out to be delicious, as well.

 

This was served with cashew chicken, choice of jasmine rice and/or farfalle pasta, some lovely fresh broccoli sautéed in garlic and extra virgin olive oil. This was followed by a simple dessert made in my food processor of fresh blueberries pureed, some Activa vanilla yogurt, sugar-free cherry jello made the day before (sets better, sitting overnight), wheat germ, and a glob of whipped cream (fat-free) on top – oh, and a crisp Sauvignon blanc.

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Enjoy!

Statement by NIH Director Francis Collins on U.S. Supreme Court Ruling on Gene Patenting

 

I am very pleased with today’s ruling by the U.S. Supreme Court in the case of Assoc. for Molecular Pathology Et Al. v. USPTO and Myriad Genetics, Inc. Et Al. that genes isolated from the human body are not patentable. The decision represents a victory for all those eagerly awaiting more individualized, gene-based approaches to medical care.

 

The right to control exclusively the use of a patient’s genes could have made it more difficult to access new tests and treatments that rely on novel technologies that can quickly determine the sequence of any of the estimated 20,000 genes in the human genome. Such approaches form the cornerstone of the rapidly emerging field of personalized medicine, in which diagnostic, therapeutic, and preventive strategies can be tailored to each person’s unique genetic makeup.

 

Francis S. Collins, MD, PHD

NIH Director