The United States Files Criminal Charges Against Orthopedic Device Manufacturers and Four ExecutivesJune 18, 2009
By Carmelina G. Allis –
We previously reported that the State of New Jersey had entered into an agreement with Synthes, Inc. to settle allegations that the company failed to disclose financial conflicts of interest among doctors who conducted clinical testing on its products. Now, Synthes has been charged by the United States government for allegedly violating several provisions of Titles 18 and 21 of the United States Code. The 58-page indictment includes conspiracy and false statement counts under Title 18, in addition to violations of the Federal Food, Drug, and Cosmetic Act by allegedly introducing into interstate commerce adulterated and misbranded devices. The indictment also charges Norian Corporation, a wholly owned Synthes subsidiary, Michael D. Huggins (President of Synthes North America), Thomas B. Higgins (Senior Vice President of Global Strategy of Synthes), Richard E. Bohner (Vice President of Operations), and John J. Walsh (Director of Regulatory and Clinical Affairs, Spine Division).
In brief, the defendants allegedly conducted clinical trials of a significant risk device without an approved Investigational Device Exemption ("IDE"), introduced into interstate commerce a device without FDA clearance or approval, and made false statements to government officials. The indictment alleges that Synthes, an orthopedic device manufacturer, purchased Norian Corporation in 1999, the manufacturer of Norian SRS, a calcium phosphate bone cement. Some time in 2000, several of Synthes’s employees allegedly conducted interviews of several surgeons with the purpose of creating a market for a version of Norian SRS with radiopaque barium sulfate for use in vertebroplasty and kyphoplasty surgeries to treat vertebral compression fractures ("VCFs"). This product was eventually marketed by defendants as “Norian XR.”
The indictment alleges that Norian SRS mixed with barium sulfate and Norian XR cannot be used on high-pressure vertebroplasty procedures, such as VCFs, because it is too thick and liquid and suspended particle components can separate/dewater. Such leakage into the venous system can allegedly cause pulmonary embolism and death. According to the indictment, prominent orthopedic surgeons had warned defendants that the Norian product in its pre-hardened state may interact with blood and cause serious adverse events, and that pre-clinical tests were recommended prior to using the product in humans. In 2002, defendants allegedly learned the results of in-vitro studies conducted on human blood that allegedly demonstrated that the Norian calcium component interacts with blood, providing both a surface on which clot could form and a chemical stimulus to clot formation.
In 2001, defendants obtained FDA clearance to market Norian SRS as a general bone void filler for bony voids not intrinsic to the stability of the bony structure. The cleared labeling warned that the Norian SRS was not to be mixed with any other substance. According to the indictment, defendants engaged in the “test market” of the Norian SRS by directing employees to create a recipe for mixing Norian SRS with barium sulfate (known as “black-table mixing”); distributing the recipe for black-table mixing of Norian SRS to spine surgeons to treat VCFs; training spine surgeons to treat VCFs with the mixed Norian SRS; directing employees to attend such training sessions; and gathering safety and effectiveness data from spine surgeons using the mixed product to treat VCFs.
FDA later cleared the Norian XR as a general bone void filler in 2002, and specifically required that the labeling include a warning indicating that the device was not intended for the treatment of VCFs. Defendants allegedly also engaged in a “test market” operation of the Norian XR for the off-label use to treat VCFs.
Between 2003 and 2004, three patients died on the operating table after suffering hypotensive episodes while using Norian XR to treat VCFs. The surgeons could not rule out Norian XR as a cause of the deaths. In all cases, Synthes Spine sales representatives were present in the operating room during the surgeries.
In 2004, FDA conducted an inspection of the Norian facility and cited the company for not having submitted an IDE prior to initiating the Norian XR “test market” and for shipping Norian XR in interstate commerce for off-label VCF uses.
The indictment alleges that the defendants conspired to approve, organize, and sponsor: (1) an illegal vertebroplasty clinical trial through a “test market” of the device; (2) surgeon forums at which spine surgeons were taught how to use Norian XR to treat VCFs; and (3) the sale of Norian XR to spine surgeons for the intended use of treating VCFs to gather an analyze safety and effectiveness information on the use of the device to treat VCFs. The indictment also alleges that defendants conspired to conceal from spine surgeons and Synthes’s own Spine sales team information that Norian SRS and/or Norian XR could accelerate blood clot formation if it escaped from bone into the venous circulation, and also failed to disclose to surgeons and sales personnel that Norian XR was contraindicated in its labeling for the treatment of VCFs. The indictment alleges that the defendants sent “dear doctor” letters to spine surgeons admitting that the use of Norian XR to treat VCFs was off-label, but that the letter omitted the thrombogenicity potential of the product and the three patients’ deaths. The indictment also alleges MDR violations and making false and misleading statements to FDA investigators regarding the off-label use of the device.
According to the press release by the United States Attorney, Norian faces a fine of $26 million and Synthes faces a fine of $8.8 million, among probation and special assessments. Each of the individual defendants faces a maximum sentence of one year in prison, a fine of $100,000, full restitution, and one year of supervised release.
All of the alleged violations occurred between 2003 and 2004.