Last week lawyers for four senior orthopedic executives asked for leniency before U.S. District Judge Legrome D. Davis as he considered how much (if any) jail time he would impose for their part in the 2003 Norian bone cement debacle.
The four former Synthes executives are Mike Huggins (former President of Synthes North America and, later, President of Synthes Spine), Richard Bohner (former Vice President of Operations for Synthes Spine), John Walsh (former Director of Regulatory and Clinical Affairs of Synthes Spine) and Tom Higgins (former President of Synthes Spine and later Synthes Vice President of Global Strategy).
All four pled guilty in mid-2009 to misdemeanor count #97 (shipping adulterated and misbranded Norian XP in interstate commerce) which carries a penalty of up to one year in prison and a $100, 000 fine.
What Went Wrong?
Synthes acquired Norian Corporation in July 1999. Norian at the time was a Cupertino, California-based start-up company founded by Stanford professor Brent Constance. His invention was an injectable, resorbable, calcium phosphate bone cement.
About the same time four miles north of Norian’s offices another company, Kyphon Inc., was revving up to enter the market for vertebral compression fracture (VCF) repair with a unique delivery system for bone cement in the spine. In 1999 the dominant bone cement was acrylic polymethylmethacrylate (PMMA)—which was being used off-label in the spine fairly routinely.
Between 1999 and 2001, Kyphon’s sales grew from $261, 000 to $36, 073, 000. Kyphon’s biggest risk was that its business relied on PMMA cement, which was not at the time approved for use in the spine (by April 2004, the FDA had cleared a PMMA for use in vertebral bodies). Furthermore PMMA is exothermic and does not remodel to bone.
Could an injectable calcium phosphate, like Norian, solve the PMMA problem for Kyphoplasty procedures?
Adapting Norian SRS for Vertebroplasty
In the spring of 2000, say prosecutors, Synthes Spine’s product development team interviewed orthopedic surgeons and others who used PMMA off-label to treat VCFs. How can Synthes improve on PMMA with its new injectable calcium phosphate? One idea was to incorporate radiopaque barium sulfate into the calcium phosphate to make it easier to see on X-rays. This new formulation was called Norian XR.
Norian XR was cleared for sale by the FDA in 2002 as a medical device to treat bone voids or defects in the skeletal system. Synthes marketed Norian XR from 2002 to 2004, selling only around 200 units and booking total net sales of approximately $400, 000.
In the meantime, Kyphon’s annual sales into the VCF market rocketed to $213 million.
Unfortunately for Synthes Spine, the marketing clearance granted by the FDA stated that Norian XR was not intended for use in the spine.
Finding the Path to the VCF Market
The prosecutors argued that the company recognized early on that there were two possible ways to get Norian XR into the VCF market. One was to ask the FDA to approve XR for use in VCR treatment and go after an investigational device exemption (IDE) to test the safety and efficacy of XR. Or, two, Synthes could arrange for surgeons to try Norian XR in VCF procedures through a limited so-called “test market, ” during which Synthes could evaluate the safety and efficacy of the product.
The federal prosecutors argued that this second path was illegal and that the Synthes executives knew it.
By late summer 2002, said the prosecutors, Synthes had approached certain spine surgeons and asked them to use Norian SRS in VCF procedures as part of an initial Synthes “test market.”
An email sent by a Synthes regulatory employees on or about August 23, 2000, to several of the indicted execs said, “[a]s everyone is well aware, I hope, we do not have a spine indication for Norian SRS at this time.” The email went on: “recently reviewed a vertebroplasty ‘Test Market’ forecast for Norian SRS and equipment sent from the spine PD…Regulatory is unaware that this is even being considered. We cannot promote the use of SRS for unapproved indications, and this is especially true for use in the spine, where the FDA has previously made it clear to Norian that any intra-spinal use would require additional approval…We are aware that the spine PD group has been considering developing a delivery system which could be used for vertebroplasty with any substance and which would therefore only be able to be used or promoted for use with autograft or allograft at this time. Such instruments would be Class I – Exempt. However, any suggestion on our part that the instrument could be used with SRS would be considered promotion of an unapproved use of SRS.”
The “Test Market” Campaign
Despite these warnings, said the indictment, the company conducted two XR “Test Market Kick-Off” surgeon meetings, and one surgeon forum from August 2003 through mid-January 2004, training approximately 52 spine surgeons to use Norian XR to treat VCFs.
Huggins, Higgins and Bohner attended the first surgeon meeting on August 15 and 16, 2003, held in San Diego with spine surgeons selected by Synthes. Lectures and PowerPoint presentations were presented by Synthes executives and attending surgeons regarding the use of Norian XR in vertebroplasty to treat VCFs. A lab was held during which the surgeons injected Norian XR into the vertebral bodies of cadavers.
A second training meeting was held in Charlotte, North Carolina, on September 19 and 20, 2003.
Patient Deaths
Sometime around June 2002 clinical investigators at the University of Washington informed Synthes and some of the defendants that they had found that the calcium contained in Norian SRS had a unique interaction with blood, providing both a surface on which clots could form and a chemical stimulus to clot formation. The pilot studies further showed dramatic clotting of a pig’s lung veins following injection of a small amount of SRS.
Six months later, December 19, 2002, the FDA cleared Norian XR as a general bone void filler with a label stating that XR was intended to fill only bony voids that were “not intrinsic to the stability of the bony structure” in the extremities, spine and pelvis, and further warning that XR was “not intended for treatment of vertebral compression fractures.”
One month later, January 13, 2003, a spine surgeon used SRS that had been back-table mixed with barium sulfate in a surgery using Synthes’s Cavity Creation instruments on a patient who became immediately hypotensive and died on the operating table. The doctor could not rule out the barium plus Norian SRS as a cause of death.
Nine months after the first patient death, on September 19, 2003, another spine surgeon used Norian XR with the Synthes Cavity Creation instrument. The patient in this case also suffered a hypotensive episode and died. In this case the doctor noted a cement leak and believed that it was the cause of the episode and could not rule out Norian XR as a cause of the death.
Throughout this period there were intensive meetings, emails and discussions at Synthes about the causes and responses to the patient deaths. Prosecutors alleged that Synthes and the defendants considered, but ultimately rejected, the idea of recalling or removing XR from the market.
Three months after the second death, on January 22, 2004, another spine surgeon used Norian XR to treat a VCF and, again, a hypotensive event occurred leading to a pulmonary embolism. This patient also died and, again, the doctor could not rule out Norian XR as a cause of death.
FDA Inspection
The FDA was watching and conducted an unannounced inspection at the Norian plant in West Chester, Pennsylvania, from May 11 through June 18, 2004. At the close of the inspection, the FDA’s investigator issued a “483” report saying, among other things, that Synthes did not submit an IDE application to the FDA prior to initiating the Norian XR “test market” and that Synthes had shipped Norian in interstate commerce for the purpose of use in vertebroplasty or kyphoplasty to treat fractures of the vertebrae, an indication for which Norian XR had not been cleared or approved by the FDA.
Guilty Pleas and Sentencing
The U.S. Attorney’s office also initiated an investigation and brought indictments against Synthes and these four senior executives in June 2009. Before summer ended that year, the defendants had entered guilty pleas.
Sentences will be handed out in the coming days or weeks. Jail time is possible. Synthes corporate paid a $23.5 million fine and was ordered to divest Norian—which they did earlier this year to Kensey Nash for $22 million.
Lessons
Every aspect of this story is tragic. What if…If only…What were we thinking?
Punishment started in 2003 for these former Synthes executives and has been continuing if not increasing ever since. Sentencing could, in some sense, be anti-climatic.
“For ’tis not in mere death that men die most.” – Elizabeth Barrett Browning
There are lessons in this story for us all. Bottom line, despite withering competitive pressures and as much as we may tug and fight with the FDA, every company and executive must abide by the letter and spirit of the FDA’s rules. Which, of course, we all know. But in middle of the battle, it can be easy to forget.
To do otherwise is to risk falling into the abyss.
