By Alleen Brown
By Maggie LaMaack
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Yee immediately responded, copying her colleagues at Daiichi in Japan. What happened in France could have a ripple effect on the entire continent and possibly trigger a safety inquiry by the Americans at the FDA. The three firms scheduled an emergency meeting in New York to discuss how to handle it.
THE KITANO HOTEL on Park Avenue in New York offered an East meets West atmosphere that formed the perfect backdrop for a meeting of scientific minds from Europe, the United States, and Japan.
But in July 2001, there was little time for soaking up the ambiance. The top drug safety executives from Daiichi, Aventis, and Ortho-McNeil had urgent matters to address.
Dr. Céline Melcion, head of global regulatory approval for Aventis, spelled out the timeline: The companies had a scant two and a half months to convince French regulators that the drug was safe. Great Britain and Belgium had also entered the fray, asking Aventis to compare the risks of its product with similar antibiotics. If the companies failed to make a strong case, Europe might restrict the drug—or ban it entirely—as soon as October.
But Aventis had a plan. Since the drug had been on the international market for many years, the company proposed an epidemiological study quantifying the medication's link to tendon problems. Researchers could simply crunch data from the millions of people who'd already taken the drug.
"The ability for retrospective studies—once a drug is on a market—can be very useful, in terms of ongoing assessment of value," says Stephen Beckman, president and general manager of the North American division of Pharmaxis, an Australian pharmaceutical company.
There was just one small problem: The databases in Europe were too small to produce conclusive results.
So Aventis planned to use data from the United States. When the Johnson & Johnson scientists heard that idea, they quickly objected. If Aventis's study yielded a connection between Levaquin and tendon rupture, the American market would be ruined.
The emergency session ended in a holding pattern. Aventis agreed to come up with a proposal for the epidemiological study and distribute it to the Americans and the Japanese for review. Billons in sales were riding on the outcome, so all the companies wanted a say in the final decision.
Two days later, Yee met with her colleagues—physicians, drug safety officers, and business development execs—back in New Jersey to plot a takeover. There was no way Johnson & Johnson was letting Aventis run this important study. According to the internal minutes from the company's defensive huddle, the study "if not conducted by J&J might be inappropriately designed, with consequences in the U.S. This will need to be managed."
By August, an Aventis epidemiologist named Drew Griffin Levy sent out a draft of the study protocol. The plan was simple enough: Levy suggested first taking a look at fluoroquinolones—the overall class of drugs that included Levaquin—and then evaluating how dangerous Levaquin was compared to the rest.
But Johnson & Johnson didn't like the Aventis proposal.
"We need to assure ourselves and Daiichi that the design of any such study is entirely appropriate, and that it will answer the question that needs answering," wrote Dr. Neil Minton, one of Yee's colleagues, "and that it will cause no harm to the product by asking the wrong questions."
Ortho-McNeil hired Ingenix, an Eden Prairie firm, to come up with an alternate study proposal. Ingenix suggested using the United Health Care database to find medical records indicating tendon repair, and to use that information to figure out the risk factors for tendon rupture among patients using the drug.
The scientists from the American company convinced their European partners that this study design was superior. They even agreed to pay for the contractor to do the work, even though the results would be used primarily in Europe.
In mid-September, as the contractors worked on their proposal, Kendall Qualls, the product director for Ortho-McNeil's line of anti-infectives, sent out an email to his colleagues. He explained that because of the French situation, the company was adding a sentence to Levaquin's FDA label that acknowledged the increased risk of tendon rupture while taking steroids.
Despite the label change, there would be no formal announcement to the employees peddling the drug, nor any alteration to the package insert, or P.I.
"There is no need to conduct teleconferences with the Field Sales Force regarding this issue," Qualls wrote. "Verbal communication to make the sales force aware will suffice. We will update the P.I. once inventories are depleted."
By late October, the Ingenix proposal was ready. Aventis used it to convince the regulators to wait for the final results before scaring European doctors with possibly unnecessary warnings.
While Ingenix worked feverishly to complete the study, Tavanic was under siege in Europe. French regulators sent a letter to doctors warning them that it could lead to cases of tendonitis and even tendon rupture. Italy mailed a similar note. And Belgium told doctors the drug should be used only for battling community-acquired pneumonia in patients who were allergic to other types of antibiotics.