Orthopedic device maker Synthes and its subsidiary Norian have pleaded guilty to organizing illegal clinical trials and promoting off-label use of Norian XR bone cement, which may have contributed to the deaths of 3 spine patients between 2002 and late 2004.

"It is in the best interests of patients, our customers, employees and the company to resolve the inquiry, and to remain focused on our important mission to improve patient care," Synthes spokesman Gilgian Eisner told Outpatient Surgery Magazine in a statement.

Norian is guilty of a felony for trying to bypass Food and Drug Administration regulations and 110 misdemeanors for shipping misbranded products; Synthes is guilty of a misdemeanor for shipping misbranded products, says the U.S. Attorney's Office in Philadelphia.

As part of the settlement signed on Nov. 30, Norian has until Dec. 9 to pay $23.5 million in fines. The parent company, Synthes, will pay $808,000 and has agreed sell off Norian, according to Swiss-owned Synthes and the U.S. Attorney's Office.

Synthes, with U.S. headquarters in West Chester, Pa., purchased Norian in 1998 and began looking for new uses for its injectable calcium phosphate bone cement, Norian SRS, which was indicated for use in the distal radius bone of the arm. In 2002, the FDA approved a new version of the cement, Norian XR, with an indication for filling non-load-bearing voids in bones.

Meanwhile, according to court documents, Synthes began interviewing surgeons who had used the cement to treat vertebral compression fractures, which was an off-label use of the product. The company then created a program that trained about 50 spine surgeons to use Norian XR in vertebroplasty and kyphoplasty procedures. The company even paid for surgeons to travel to San Diego, Calif., and Charlotte, N.C., in 2003 to attend presentations on using the cement in vertebroplasty procedures and participate in cadaver labs where surgeons injected the cement into vertebrae.

Rather than file for an investigational device exemption that would allow the company to sponsor clinical trials with the cement, executives at Synthes decided to "get a few sites to perform 60-80 procedures and help them publish their clinical results," according to a federal indictment filed in June 2009.

Synthes continued promoting off-label use of the cement in the spine even though studies on human blood in test tubes showed that the cement caused blood clotting, the indictment says. Another study showed "dramatic clotting of a pig's lung veins."

In January 2003, during a vertebral compression fracture procedure using the cement mixed with barium sulfate, the patient became immediately hypotensive and died in the OR. Two other patients died similarly on the operating table in September 2003 and January 2004. A Synthes rep was in the room when each death occurred, say court documents. After the third death, the "test market" program was scrapped.

Later in 2004, Synthes voluntarily removed Norian XR from the market. Norian cements with other indications remain on the market and are used safely for their indications, said Mr. Eisner, adding that a buyer for Norian has yet to be announced.

"Device manufacturers have a legal obligation not to test their devices on humans without FDA oversight," said U.S. Attorney Zane David Memeger in a statement announcing the plea agreement. "This case is especially troubling because in search of greater profits, Norian bypassed this process."

Kent Steinriede

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