Patients suffered. Their throats swelled shut. They had to undergo corrective surgeries. Men experienced infertility.

Now, the financial connections between the company and the doctors are the focus of a federal probe, a congressional inquiry and a public purging. New questions arise about whether doctors and the medical industry can be trusted to prove the safety and effectiveness of new products. And the controversy casts another pall on the Memphis-based medical device industry.

The doctors who did the studies and wrote the articles about Infuse in medical journals received support from Medtronic ranging from $1 million to more than $23 million.

“Can we accept industry-sponsored studies as the basis to go full bore into the use of a product?” said Dr. Dan M. Spengler of Vanderbilt University. “I’m suggesting probably not, based on our experience here.”

Andrew Carr, a lawyer who filed a whistle-blower lawsuit on behalf of former Medtronic employees in Memphis, said the corporate culture within the highly competitive orthopedics industry is at the heart of the problem.

“Sure the culture must change, but that can only change when the penalties, both civil and criminal, become meaningful deterrents,” Carr said. “Otherwise, the continuing hand-slaps and fines will continue to represent the cost of doing business.”

The Spine Journal this summer dedicated an entire issue to setting the record on Infuse straight. Two U.S. senators demanded to see all the communications between Medtronic and the doctors.

In response, Medtronic last week hired Yale University for $2.5 million to review the safety and effectiveness of Infuse. All the while, a U.S. attorney’s investigation has been ongoing since 2008.

The journal’s review of the data behind 13 previously published studies found that side effects occurred 10 percent to 40 percent of the time, depending upon how Infuse was used. The authors of the original studies reported no adverse events.

Spengler wrote an editorial in The Spine Journal calling for better supervision of clinical trials and more transparency by the doctors who conduct them, the editors who accept their studies and the other physicians who review their conclusions before publication. He noted that a surgeon from Croatia found one inconsistency simply by reading one of the articles.

‘Off-label’ use risky

The studies that have drawn the most criticism supported Infuse for “off-label” purposes. The U.S. Food and Drug Administration in 2002 approved Infuse — a special protein applied to a collagen sponge and placed next to vertebrae to promote bone growth — for use within small metal cages the size of thimbles. But the use was approved only for the lumbar region of the spine, the lower back.

“It’s a great product,” said Dr. Jason R. Hubbard, a Nashville neurosurgeon. “It works very well. It saves you from having to take bone grafts from a person’s hip, which is very painful.”

Doctors began promoting the product for “off-label” uses after conducting Medtronic-sponsored studies. From 2002 to 2006, the usage of Infuse grew from 0.7 percent of all spinal fusions to 25 percent, according to The Spine Journal.

One of the “off-label” uses advocated was in the neck. By 2007, the product was in 18 percent to 20 percent of these neck surgeries. But some patients’ throats swelled shut two to 14 days after the surgery. The FDA in 2008 issued a warning of life-threatening complications from the bone protein.

The Spine Journal determined that the risk of complications from use of the protein in the neck surgeries was 40 percent to 50 percent higher than without it.

Side effects reported with other types of spinal surgeries using Infuse include wound complications, leg and back pain, infections, loss of bone tissue, retrograde ejaculation in men (in which semen enters the bladder) and increased cancer rates when the protein was used in higher dosages.

Transparency grows

Omar Ishrak, chief executive officer of Medtronic, issued a statement in response to The Spine Journal issue.

“Integrity and patient safety are my highest priorities,” Ishrak said. “While The Spine Journal articles raise questions about researchers’ conclusions in their peer-reviewed literature, the articles do not raise questions about the data Medtronic submitted to the FDA in the approval process or the information available to physicians today through the instructions for use brochure attached to each product sold.”

Medtronic has taken measures to be more transparent. In March, it began posting the names of doctors who receive payments from the company and the amount they receive. The list is limited to payments made in 2010.

Hubbard did not show up on that list. But he did make $50,000 from the company during a prior year, training other surgeons in how to use Infuse for minimally invasive lower back surgery.

“Surgeons need to be trained,” Hubbard said. “So how do we get one surgeon to train another surgeon? You’ve got to pay that surgeon. It’s a daily rate. How do you avoid the appearance of evil that you are giving some doctor a kickback?”

Scandals aren’t new

Scandals about kickbacks to doctors are almost old news within the medical implant industry. Two other companies with operations in Memphis have entered into deferred prosecution agreements with federal investigators and had presidents resign. Besides payments and gifts to doctors, two of the companies, including Medtronic, have been accused of taking doctors to strip clubs.

The lawsuit that Carr filed in 2007 accused the company of giving kickbacks to doctors for promoting Infuse. The lawsuit got dismissed because his clients were not the first to sue. Two other former Medtronic employees previously filed suit, although their allegations did not involve Infuse. The federal whistle-blower statute prevents piggyback suits after any wrongdoing has been publicly disclosed.

The earlier lawsuit alleged that Medtronic set up bogus royalty agreements with doctors, established consulting agreements as fronts and paid for trips to Alaska; Cancun, Mexico; Hawaii; Malaysia; and New Orleans during Mardi Gras. Medtronic settled the civil suit in 2006 by agreeing to pay the United States $40 million.

Last October, Wright Medical Group Inc., also based in Memphis, avoided prosecution for allegedly violating the federal kickback statute when it agreed to pay $7.9 million to the federal government and have its relationships with surgeons monitored. In April, CEO Gary Henley abruptly resigned and the company fired its chief technology officer for “failing to exhibit appropriate regard” for its compliance agreement.

Smith & Nephew, whose global spinal and biologics business is based in Memphis, entered into a deferred prosecution agreement in 2007 along with four other medical implant companies. That company paid a $28.9 million fine and agreed to be monitored.

Two years later, Smith & Nephew executive Andrew Holman lost his job along with salesmen after the company’s compliance department investigated a trip to a strip club with a doctor client, according to another federal lawsuit.

Medtronic has issued a statement that it will comply with requests from U.S. Sens. Charles Grassley, R-Iowa, and Max Baucus, D-Mont., for information about Infuse. The company noted that the FDA-approved labeling for Infuse warns of the potential side effects the senators wrote about in their letter to the company.

“Medtronic to their credit has been trying to do it the right way,” Hubbard said. “They got caught in this controversy and they are trying to play it backwards. They are trying to go backwards and do the right thing.”