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Ellen Klepac
Ellen Klepac
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When Medical Device Manufacturers Market Off-Label

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After multiple fatalities, crimes, lawsuits, and imprisonments, the courtroom battles still rage between medical device company Synthes and families of the patients who were killed by its dangerous drug, according to an October 2012 article published in Fortune magazine.

Synthes, based in West Chester, PA, specializes in producing the plates and screws used in bone surgeries. The company was founded as a research organization by four Swiss surgeons in 1958. During the 1970s, one surgeon hired Hansjörg Wyss, a Swiss businessman, to run the company’s U.S. operations. Wyss gradually turned the company into an industry giant and became both CEO and multibillionaire.

In 1999, under Wyss’ guidance, Synthes purchased Norian, a young biotech company that had developed a special kind of cement used to repair bones. Unlike existing cements, Norian’s turned into actual bone after being injected into cracks in the skeletal system. At the time of the purchase, Norian had already received FDA approval for two of its bone cements to be used in the arm and in the skull.

A further use, for which Norian hoped to get FDA approval, provided further incentive for Synthes to buy the company. Executives felt the Norian cement had tremendous potential to make the company a lot of money in vertebroplasty, or using the cement to fill cracks in the spine that were often caused by vertebral compression fractures, a common occurrence in patients with osteoporosis. At the time, a large number of surgeons were promoting the procedure, but Norian had not yet been successful in convincing the FDA of the cement’s safety. After Synthes acquired Norian, the FDA informed the company that it would have to conduct clinical trials on willing patients. Those trials would take a lot of time and money.

It was at this point that Synthes made the first of its subsequent long line of ill-fated decisions. Wyss decided to forego clinical trials and instead announced in a company meeting that Synthes would promoting the Norian cement for use in vertebroplasties. The announcement reportedly raised a red flag for many employees. Without FDA approval, marketing a product was illegal. Employees weren’t even allowed to tell physicians about a product’s uses if it had not been FDA-approved. Contrary to the announcement, executives assured concerned employees that Norian was not going to be promoted for use in the spine.

In April 2001, however, Synthes Spine President Tom Higgins organized an event for surgeons interested in using Norian in vertebroplasties. Discussed was the fact that one surgeon had already used it in two procedures two months prior to the event. Those patients had suffered vertebral compression fractures, and, in both instances, the patients’ blood pressure plummeted after Norian was injected. An anesthesiologist allegedly had to give the patients drugs in order to keep them alive.

Another surgeon, Dr. Sohail Mirza, suggested that Synthes conduct animal studies to see if cement leaked into the bloodstream when injected. If Norian got into the bloodstream via blood vessels throughout the spine, it had the potential to form a fatal clot in the heart or lungs.

Synthes provided Mirza and colleague Dr. Jens Chapman funding to perform that animal study. In the meantime, Synthes attempted a different form of FDA approval. Rather than performing the necessary clinical trials to have Norian approved for vertebroplasties, Synthes completed an easier regulatory process typically used for “modifications of permitted devices.”

In December 2001, the FDA approved Synthes’ bone cement for use in the spine – with an important stipulation: It could not be mixed with any other substances prior to injection. But this mixture of substances was the very thing the procedure of vertebroplasties depended upon. Thus, the company was blocked from marketing its medical device for the appealingly lucrative use it had bought Norian for in the first place.

Mirza and Chapman’s study results were no more encouraging. They found that as soon as a small amount of Norian was injected into a pig’s bloodstream, blood clots formed and shut down the pulmonary artery system, which carries blood from the heart to the lungs. The pig died within seconds. The researchers also mixed Norian and human blood in test tubes, which resulted in a large amount of blood clots.

In spite of the research results and associates who were aware of the dangers of pushing ahead with the Norian marketing plan, CEO Wyss, president Higgins, and the head of Synthes’ North American division, the company decided to do just that. Such off-label marketing is rampant in medicine, since time can run out for a patient before a product receives FDA approval. According to the Fortune article, surgeons are often more likely to follow the promptings of medical device sales representatives than FDA regulations.

As one former Synthes employee said, “It’s not uncommon to have a surgeon with a drill in his hand, about to drill a hole, looking over his shoulder at you saying, ‘Is this right?’”

Synthes proceeded with its own toned-down form of trials and trained groups of surgeons on how to mix Norian with barium sulfate for use in vertebroplasty, despite the FDA’s explicit guidelines. Norian bone cement was put to use by many of the surgeons trained, and for a time, every surgery seemed to end in success. Synthes even received FDA approval in December 2002 for the mixed version of Norian, called Norian XR. Like the original, the FDA restricted the use of Norian XR in treating vertebral compression fractures and required that the product warning label say as much. Also like the original, this demand went unheeded.

Less than a month later, disaster struck. Dr. Barton Sachs used Norian to treat the vertebral compression fracture of his patient, 70-year-old Lois Eskind. Seconds after Norian was injected, Eskind’s blood pressure dropped. After 30 minutes of attempted resuscitation, Eskind was pronounced dead. Sachs did not blame Norian, and Eskind’s family did not request an autopsy. But when Synthes inquired into the incident, Sachs expressed his doubts. Minutes of the call recorded him as saying that he performed the surgery as instructed, “and the outcome was catastrophic.”

FDA regulations require companies to report deaths or injuries involving their medical devices, but Eskind’s death was not reported.

In August 2003, Synthes held another event for surgeons to promote Norian XR and train them how to inject the mixture into the spine. Following the event, Norian again was used successfully by several surgeons.

But on September 19, history repeated itself. Dr. Paul Nottingham injected Norian XR into 83-year-old patient Ryoichi Kikuchi, whose blood pressure immediately plummeted. He died on the table after Nottingham’s failed resuscitation attempts. Nottingham could not prove the death was caused by Norian, but unlike Sachs, he had no qualms about blaming Kikuchi’s wrongful death on the product. He reportedly told Synthes that the sales representative had been deceitful, and he would never use Norian again. Synthes reported the death to the FDA this time, but the report was “vague and left out key details,” according to Fortune.

On January 21, 2004, another patient, 83-year-old Barbara Marcelino, died after being injected with Norian. Her surgeon, Dr. Hieu Ball, was Nottingham’s partner. The earlier deaths were known to Norian product managers and executives, but now word got out to other Synthes employees, causing alarm.

In May 2004, Capt. Joseph Despins, an FDA investigator, showed up at Synthes headquarters. Over the next month, he interviewed executives and staff (most of whom denied everything, according to the Fortune article). At the conclusion of his investigation, he submitted a 143-page report that accused Synthes of off-label marketing and violating FDA regulations.

After nearly five years of FDA investigations, the government indicted Synthes and four executives. The executives pled guilty to a misdemeanor under the Responsible Corporate Officer Doctrine, which allowed individuals in positions of leadership to be charged in cases of “public danger,” even if it could not be proven that they knew about or committed a crime.

On June 16, 2009, Norian (the company) was charged with 52 felony counts, while Synthes was charged with 44 misdemeanors. The four executives were charged with a single misdemeanor, but the battle between the U.S. prosecuting attorney and the executives’ attorneys went on for two years.

In October 2010, Synthes pled guilty and was fined $23 million. Over a year later, in November 2011, the four Synthes executives were given an unprecedented prison sentence, ranging from five to nine months. The sentences rocked an industry in which fines were not only accepted but viewed as “a cost of doing business.”

When sentencing one executive above federal guidelines, Judge Legrome Davis said, “I think that a lesser sentence would not speak to the harm that has been done here. … [W]hat has occurred in this case, in terms of wrongfulness – it’s 11 on a scale of 10.”

Though Wyss was not initially charged, a number of victims’ families have sued him and Synthes. Other Norian victims have also recently come into the picture, thanks to the fact that the indictment did not put a stop to surgeons using Norian in spinal procedures.

*For information about another company, Medtronic, marketing its Infuse Bone Graft for off-label, or unapproved, procedures (and currently pending Medtronic lawsuits), watch this brief video: http://youtu.be/xzvT6g-1MbQ