Inspection Triggers FDA Warning Letter to Smith & Nephew

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A March inspection of the manufacturing facilities of medical device maker Smith & Nephew have resulted in a Food and Drug Administration (FDA) warning letter to the company based on problems observed during an inspection.

FDA inspectors discovered problems with arthroscopy (joint replacement) and gynecology devices, including the TRUCLEAR ULTRA Reciprocating Morcellators 4.0.  

Section 201(h) of the Federal Food, Drug, and Cosmetic Act defines devices as products “intended for use in the diagnosis of disease or other conditions or in the cure, mitigation, treatment, or prevention of disease, or to affect the structure or any function of the body.” In the letter, Joseph Matrisciano, the acting district director for the FDA’s New England regional office, explains that a number of Smith & Nephew devices are “adulterated” under the meaning of section 501(h) of the law because “methods used in, or the facilities or controls used for, their manufacture, packing, storage, or installation are not in conformity with the current good manufacturing practice requirements.”

Smith & Nephew “failed to establish and maintain procedures for verifying or validating corrective and preventive actions (CAPA) to ensure that such action is effective and does not adversely affect the finished device, as required by 21 CFR 820.100(a)(4).” For example, Matrisciano wrote, eight corrective action reports were reviewed during the inspection and they did not contain sufficient information to ensure corrective actions were completed and verified as effective.

The company must address problems including an incorrect translation of the term, “non-absorbable suture” in the IFU for TwinFix Ultra Preloaded Suture Anchors; an increased complaint rate for Beaver Blade device breakage in the field; and a large number of complaint investigations that had been open for greater than 90 days.  At the time of the inspection, the FDA said, there was no documentation that all open action items had been completed.

The FDA deemed Smith & Nephew’s response inadequate because the company did not provide complete documentation of corrections. Smith & Nephew has fifteen business days from receipt of the letter to respond and provide specific steps the firm has taken to correct the noted violations, as well as an explanation plans to prevent these violations, or similar violations, from occurring again. The company must include documentation of the corrections and/or corrective actions, must address systemic problems, and must include a timetable for actions that will “occur over time.”  If corrective actions cannot be completed within fifteen business days, Smith & Nephew must give reasons and state the time within which these activities will be completed.

The FDA wrote that failure to promptly correct these violations may result in regulatory action including, but not limited to, seizure, injunction, and civil money penalties. In addition, Smith & Nephew’s premarket approval applications for Class III devices to which the regulation violations are “reasonably related” will not be approved until the violations have been corrected.  Certificates to Foreign Governments will not be granted until the violations related to the subject devices have been corrected.





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12-Year-Old Girl Awarded $15 Million for Birth Defects Caused by Depakote, Which Her Mother Took During Pregnancy

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Maddison Schmidt, 12, has spina bifida and numerous other birth defects. This week, a St. Louis, Missouri, jury agreed with her family that the drug Depakote, which Schmidt’s mother took while she was pregnant, caused her health problems and awarded the girl $15 million.

The unanimous verdict arrived Tuesday. The jurors, who began deliberations on Friday, are now determining whether to award Schmidt punitive damages. The girl’s family claimed in the lawsuit that Abbott, the maker of Depakote, downplayed the dangers of the drug, and that the medication was defectively designed and inadequately tested, according to St. Louis Post-Dispatch (Post-Dispatch).

“Abbott steadfastly refused to communicate the true nature and extent of the risk in its product labeling and warnings to physicians and consumers,” the suit, obtained by Post-Dispatch, states.

Maddison Schmidt is only one of two dozen plaintiffs listed in the suit. Though Abbott is named in the suit, AbbVie Inc. is the financially responsible party in the verdict, as Abbott spun off its branded drug business to the company in 2013, regulatory filings viewed by Post-Dispatch indicate. At the time of the spinoff, Abbott required AbbVie to assume business-related liabilities that occurred before the spinoff, according to the company’s annual report filed with the U.S. Securities and Exchange Commission, which Post-Dispatch obtained.

“With the separation the commercial rights and associated responsibilities for Depakote passed to AbbVie,” a statement provided by Illinois-based Abbott reads.

A safety announcement was issued by the U.S. Food and Drug Administration in 2013 warning that pregnant women should not use sodium valproate drugs, including Depakote. The agency said would-be mothers should avoid using the class of drugs to prevent migraines, in particular. The announcement was spurred by a then-recent FDA study that found sodium valproate drugs can decrease children’s IQ scores, Post-Dispatch reported.

The agency also said at the time that Depakote and other sodium valproate drugs should only be used by pregnant women suffering with epilepsy or bipolar disorder if other medications were not effective or deemed inappropriate, according to Post-Dispatch.

Abbott agreed in 2012 to pay the federal government $1.5 to settle allegations that the drugmaker had unlawfully promoted Depakote for “off-label” purposes not approved by the FDA. The company allegedly marketed the drug to elderly patients with dementia and patients with schizophrenia. In a 2012 U.S. Department of Justice statement obtained by Post-Dispatch, the agency said that Depakote was approved only for the treatment of epilepsy, bipolar disorder and migraines.

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Prolonged Use of Tylenol While Pregnant May Cause Infertility in Baby Boys

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A new study published in Science Translational Medicine shows that pregnant women who use Tylenol for prolonged periods of time may give birth to baby boys with fertility problems.

Scientists at the University of Edinburgh in the United Kingdom grafted human testicular tissue onto mice, and then divided them into two groups: one group received acetaminophen, the main ingredient in Tylenol, for 24 hours, and the other group was given the daily drug for seven days. After measuring testosterone production an hour after the last dose in both groups, scientists observed no effect in the mice given acetaminophen for 24 hours. This was not the case in the second group, however; the team found that group had a 45 percent reduction in testosterone, according to Toronto Sun.

Tylenol is popular among pregnant women because it has for years been considered a safe, over-the-counter (OTC) painkiller. According to university researchers, lower exposure to testosterone in the womb has been linked to a greater risk of male infertility, undescended testicles and testicular cancer. While the study was performed only in animals, the scientists are urging pregnant women to be cautious about the length of time they take Tylenol for aches and pains.

“We would advise that pregnant women should follow current guidance that the painkiller be taken at the lowest effective dose for the shortest possible time,” Dr. Rod Mitchell of the University of Edinburgh said in a news release obtained by Toronto Sun.

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University of Massachussetts Amherst Epidemiologist Examines Possible Connection Between Phthalates and Breast Cancer

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A University of Massachussetts Amherst epidemiologist has been awarded a three-year, $1.5 million grant to investigate a potential link between phthalates and breast cancer.

Phthalates are plasticizing, solvent chemicals found in products such as cosmetics, shampoos, flooring and medical tubing. Scientists have wondered for a long time whether phthalates impact human breast cancer risk, but lacked reliable data to draw a conclusion. Epidemiologist Katherine Reeves is on a mission to investigate phthalate metabolites – products found in urine samples after the chemicals have passed through the body – as nearly 100 percent of the U.S. population has measurable phthalate metabolites in their bodies, according to The Recorder.

Only a small handful of studies have examined whether phthalates affect human breast cancer risk, and none of them measured phthalate metabolites before a cancer diagnosis. For the study, Reeves, along with UMass Amherst biologist Thomas Zoeller, an expert in endocrine-disrupting chemicals; epidemiologist Sue Hankinson, and biostatistician Carol Bigelow will analyze levels of 11 phthalate metabolites in urine samples collected from 500 women with invasive breast cancer after Year 3 of follow-up and in 1,000 healthy matched controls. The study is nested within the Women’s Health Initiative, The Recorder reported.

“This study, where the samples were given many years before any sign of disease appeared, will give us much stronger evidence in terms of causality than studies using another design,” Reeves told The Recorder.

Researchers stored urine samples from baseline, Year 1, Year2 and Year 3, which will allow them to address variation in phthalate exposure. Reeves told The Recorder that she hopes “to provide not more uncertainty, but instead either reassurance or solid evidence of cause for concern” through the study. “It is well designed and large enough so no matter what answer we find we can have confidence in the result,” she added.

The study will seek to determine whether associations between phthalate metabolite levels and breast cancer vary by disease characteristics like hormone receptor status and personal factors including, age, postmenopausal hormone therapy use and body mass index, The Recorder wrote.

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Boy’s Future Fertility Could be Affected by Mother’s Acetaminophen Use in Pregnancy

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A study from the United Kingdom, published in Science Translational Medicine, suggests that prolonged exposure to acetaminophen during pregnancy could lower a boy’s production of testosterone, possibly affecting his future fertility.

If the expectant mother takes acetaminophen for several days it could affect her unborn boy, lowering his future sperm count, Medical News Today (MNT) reports. Acetaminophen is a widely used over-the-counter pain-reliever and fever-reducer that is sold under brand names including Tylenol and in generic and house brands.

The study’s authors explain that the risks of low testosterone in developing male fetuses include such disorders as undescended testis (cryptorchidism) and hypospadias, a urethral malformation in which the urine outlet is not in the normal position at the end of the penis. In young adulthood, the boy could experience low sperm counts and testicular germ cell cancer can develop, according to MNT.

Pediatric endocrinologist Dr. Rod Mitchell, a Wellcome Trust clinical research fellow at the University of Edinburgh and one of the study authors, says the study “adds to existing evidence that prolonged use of acetaminophen in pregnancy may increase the risk of reproductive disorders in male babies.” If a pregnant woman needs acetaminophen, she should take “the lowest effective dose for the shortest possible time,” Mitchell says.

To examine the effects of acetaminophen on testosterone production, Dr. Sander van den Driesche and colleagues at the MRC Centre for Reproductive Health at the University of Edinburgh grafted fragments of human fetal testes into castrated mice. Xenograft—the surgical grafting of tissue from one species to an unlike species—allowed the researchers to avoid problems in trying to measure testosterone production in unborn human males. The authors say their model “reflects physiological development and can be used to test the effects of chemical exposures on testosterone production,” according to MNT.

To conduct the experiment, the researchers gave the grafted mice a dose of acetaminophen equivalent to a human dose of 20 mg per kg three times a day for seven days. Testosterone levels in their blood dropped by 45 percent and the weight of the seminal vesicle glands fell by 18 percent. Seminal vesicles secrete the semen fluid, and the researchers used the weight of the vesicles as a biomarker of exposure to testosterone. The results were compared to those for mice receiving a placebo that contained no acetaminophen. Exposure to acetaminophen for a single day did not affect the measures of testosterone production.

While the researchers say further research is needed to understand how acetaminophen affects testosterone production in male fetuses, they advise caution in extended use of acetaminophen in pregnancy. Dr. Martin Ward-Platt of the Royal College of Paediatrics and Child Health says fever during pregnancy can be harmful to the developing fetus and so acetaminophen is sometimes necessary, according to MNT. But Dr. Ward-Platt says pregnant women should avoid prolonged acetaminophen use and “should always consult with their health care professional before taking any prescription or over-the-counter medicine.”


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Medtronic to Pay $4.4 M to Settle False Claims Act Lawsuit

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Medtronic will pay $4.4 million to settle alleged violations of the False Claims Act, the U.S. Department of Justice said. Medtronic allegedly made false statements involving the sale of medical equipment to the U.S. Department of Defense and the U.S. Department of Veteran Affairs from January 2007 to September 2014. Under United States law, devices sold to the military must be manufactured in the U.S. or by its international trading partners. According to allegations, Medtronic sold equipment manufactured in China and Malaysia and falsely claimed that it originated from the U.S.

“Today’s settlement demonstrates our commitment to ensure that our service members and our veterans receive medical products that are manufactured in the United States and other countries that trade fairly with us,” Acting Assistant Attorney General Benjamin C. Mizer of the Justice Department’s Civil Division stated. “The Justice Department will take action to hold medical device companies to the terms of their government contracts.”

“Congress has said that when you sell products to the government, that they must be made in the United States, or in a country that we have a free-trade agreement with,” said Assistant U.S. Attorney Ann Bildtsen, according to Star Tribune. “And companies certify to that … and those certifications need to mean something. This case sends a message that they mean something to the government.”

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