The success of a Public Citizen lawsuit may hinge on whether the advocacy group can convince a judge that 16 months is an "unreasonable delay" in acting on a petition requesting labeling changes.

The public interest advocacy group filed a suit in the U.S. District Court for the District of Columbia Jan. 3 against FDA, stating that FDA's failure to respond to its petition "constitutes agency action unlawfully withheld or unreasonably delayed and violates the Administrative Procedure Act."

The lawsuit is the latest clash between Public Citizen and FDA in a decade-long fight over fluoroquinolone antibiotics and an associated risk of tendon rupture, entangling industry and even the Illinois Attorney General's office.

Fluoroquinolones, including Bayer's Cipro (ciprofloxacin) and Johnson & Johnson's Levaquin (levofloxacin), have had tendonitis and tendon rupture warnings on package inserts since 1996, a year after FDA began negotiating with manufacturers (¹ Also see "Quinolone antibiotic labeling to include warnings of potential tendon inflammation/rupture." - Pink Sheet, 5 August, 1996., p. T&G-1).

FDA disclosed the label change talks after Public Citizen filed a citizen petition Aug. 1, 1996, requesting FDA "immediately require a warning in bold type in the official product labeling" of quinolones.

At the time, FDA determined a MedGuide and "Dear Doctor" letter were not warranted as the risks were not common enough adverse events and the label change along with letters to medical journals would be sufficient for physician awareness.

Upping The Ante

Ten years later, Public Citizen echoed a citizen petition filed by the Illinois Attorney General's Office, who in May 2005 urged FDA to add a black-box warning to fluoroquinolone labels.

Although Public Citizen stated in 1996 they successfully petitioned FDA to get warnings on the label, the new ² petition, filed in August 2006, claimed the changes were "grossly inadequate" and "buried in a list of possible adverse reactions."

The 2006 petition included an analysis of FDA's adverse event database, which reported 262 cases of tendon rupture, 258 cases of tendonitis and 274 cases of other tendon disorders from November 1997 through December 2005.

"The demographics of tendon rupture are vastly different," the petition stated, citing data showing fluoroquinolone-associated ruptures occurred in older females, whereas in the general population, such events tend to occur in younger males.

"It's not a complex issue," Sidney Wolfe, director of Public Citizen's Health Research Group, told "The Pink Sheet," calling the demographics "proof-positive" that there needs to be a stronger warning. "If you need proof of causation, it's there."

Yet while the association of adverse tendon events with fluoroquinolone use is "well-documented," musculoskeletal researcher Wan-Fai Ng, University of Newcastle, told "The Pink Sheet," "it is uncommon."

Public Citizen also requested FDA issue a "Dear Doctor" letter and require an approved MedGuide when prescriptions are dispensed.

FDA responded to Public Citizen in February 2007, saying it was unable to reach a decision on the petition because it raised "complex issues requiring extensive review and analysis by agency officials."

Is Time On FDA's Side?

The case claims FDA violated the Administrative Procedure Act, attorney for the plaintiff Michael Kirkpatrick told "The Pink Sheet." Under the APA, 5 U.S.C. § 706(1) and (2)(A), a court can "compel agency action unlawfully withheld or unreasonably delayed; and hold unlawful and set aside agency action, findings, and conclusions found to be ... not in accordance with the law."

"FDA's delay in ruling on the petition becomes increasingly unreasonable with the passage of time," Kirkpatrick said, and Public Citizen "has waited long enough for a ruling and has resorted to litigation to force FDA to do its job and act on the petition."

FDA's interim response, which Wolfe dismissed as "punting," may be enough to satisfy a judge, but a judgment in favor of Public Citizen could still result in an FDA denial to add the black-box warning.

If that happens, Kirkpatrick said, Public Citizen "will have to consider FDA's reasons for such a denial and then determine what PC will do."

- Becky Jungbauer (r.jungbauer@elsevier.com)

Seeking Stronger Antibiotic Warnings, Public Citizen Sues FDA

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