Synthes' relationship with surgeons questioned

Synthes Inc. handpicked the surgeons.

The West Chester maker of orthopedic products also paid for the doctors' travel to training sessions in San Diego and Charlotte, N.C.

There, company employees explained how to use their new bone-mending cement to fix a type of spinal fracture that afflicts hundreds of thousands of people yearly, most of them elderly.

Federal prosecutors alleged in an indictment of the company last week that these training sessions were a dangerous, illegal, and less expensive substitute for clinical trials required by the Food and Drug Administration. Synthes has said it acted properly and will defend itself against the charges.

The indictment casts a spotlight on the cozy and lucrative relationships between doctors and makers of drugs and medical devices. The allegations, if true, also illustrate how a company can exploit regulatory gray areas to boost sales while undermining patient safety.

The Norian XR surgeries fell into a category known as "off-label" promotion. The FDA approves drugs and devices for certain purposes - Lipitor to lower cholesterol, or a stent for certain heart surgeries. Those are "on-label" uses.

While doctors can prescribe a drug or device for any use, federal rules forbid companies from promoting their medical products for off-label uses, even if doctors already use them that way.

And that, the indictment says, is where Synthes ran afoul of the law.

It allegedly marketed Norian XR for surgeries to treat vertebral compression fractures, a use not approved by the FDA. That promotion led to 200 surgeries in which three people died, although prosecutors said they could not determine what role, if any, the bone cement played.

The FDA had approved Norian XR for other types of surgeries but worried that, because spines bear so much body weight, the cement could leak and cause blood clots.

Off-label promotion is a tricky area. Sales representatives cannot suggest an off-label use, for example, but if a doctor asks questions about it, they can answer.

Drug- and device-makers can manipulate these ambiguities to boost sales without spending millions on clinical trials, experts in medical research said. Companies pay doctors who are considered leaders in their fields to give speeches discussing a product and can mention an off-label use, for example.

"It's an attempt to do an end-run around the approval process," said Peter Lurie, deputy director of Public Citizen's Health Research Group, which advocates for patient safety.

Arthur Caplan, bioethics chairman at the University of Pennsylvania, said such end-runs may be easier with surgical devices. Surgeons often experiment to see what will work, he said.

"What a company can do is get a ton of off-label use going, and just let it go," Caplan said. "Surgeons start whispering to other surgeons, and then the company can simply tell the FDA, 'We didn't encourage it.' "

The controversies have seemed especially common in orthopedics recently.

Last week, Medtronic Inc., a maker of medical devices, said it paid about $800,000 in the last three years to a former Army surgeon accused of fabricating a study that reported positive results for one of the company's key spine products. The federal government is investigating Medtronic's payments to surgeons. The Minneapolis company has denied wrongdoing.

Synthes has run into regulatory trouble before, too. In May, it settled charges brought by the New Jersey attorney general for failing to disclose financial relationships with doctors researching its products.

The company did not admit any wrongdoing. The attorney general said Synthes had failed to disclose that many of the researchers who conducted trials on its Prodisc artificial spinal disk also were investors who stood to profit if the device sold well. One of those investors was Jack Zigler, a well-known surgeon at the Texas Back Institute in Plano, according to a January 2008 New York Times article.

One of the people who died while undergoing surgery involving Norian XR was a patient at the Texas Back Institute, the Philadelphia U.S. Attorney's Office said. Prosecutors did not charge the Texas Back Institute or any other medical facilities or doctors.

Through a spokeswoman, Texas Back Institute president Richard D. Guyer said his organization "will never compromise the best and safest treatment for every patient." He would not answer further questions.

Last week's indictment suggests a tight relationship between Synthes and surgeons. The test surgeries allegedly began in 2002 and continued until a third patient died in January 2004. Synthes sales representatives were in the operating rooms during some surgeries, a practice medical experts said was common.

Federal law requires that patients involved in research give informed consent, which includes making sure the patient understands the risks involved in experimental procedures. It is not clear that patients knew the risks in using Norian XR in these surgeries.

"Informed consent is a bedrock principle of clinical research," said Hal Sox, editor of the Annals of Internal Medicine, a medical journal published in Philadelphia.

One of the surgeons whose patient died told Synthes executives that he had "noticed a cement leak during injection and feels this was the cause of the incident," according to the indictment. The surgeon complained that a Synthes "sales consultant pushed this product on him and was unclear as to its status on the market."

Synthes executives allegedly failed to report the first patient death to the FDA, as required by law, and left out key details when they reported the two other deaths to hide off-label promotion of Norian XR, the indictment said.

In November 2004, Synthes told the FDA it was going to take Norian XR off the market. Company spokesman Gilgian Eisner said yesterday that it did so "out of an abundance of caution."

In its notice to the FDA about the decision, the company said: "After review of all info reasonably known to synthes, it was determined that device involvement is possible, but not definitive."