One of the more contentious elements of Eli Lilly's application for Cymbalta (duloxetine) in chronic pain is exposing a much larger population to a risk of hepatotoxicity.

FDA's application reviewer disagreed with higher-ranking agency officials on whether a black-box warning was necessary for the new indication. Briefing documents posted ahead of the Aug. 19 meeting of the Anesthetic and Life Support Drugs Advisory Committee illustrated the conflict in three separate memos authored by the agency officials.

Reviewer Marc Stone felt Cymbalta was more likely to cause a serious adverse event like hepatic failure than other drugs intended to treat the same condition and should have a boxed warning.

Stone said laboratory and clinical data indicate liver injury can be attributed to Cymbalta. He said there were more than a dozen case reports strongly showing the drug as the cause of acute non-fatal hepatic failure as well as several cases of death from hepatic failure while taking Cymbalta that could be due to the drug, but other potential causes could not be ruled out.

However, Victor Crentsil, acting deputy director for safety, Division of Psychiatry Products, disagreed, saying the current label includes information on hepatotoxicity in the "Warnings and Precautions" section. He said the case reports Stone reviewed did not indicate new safety information and argued Stone's review did not prove an association between Cymbalta exposure and severe liver injury.

Thomas Laughren, director, Division of Psychiatry Products, agreed with Crentsil in a separate memo, saying the current labeling is a "fairly strongly worded statement alerting prescribers to the risk of significant liver injury."

Laughren said Cymbalta requires continued monitoring for hepatotoxicity, but no case has been made to justify the addition of a boxed warning. He said the only reason for a boxed warning would be because the agency has decided Cymbalta should not be used as a first-line treatment for its approved indications.

"Although there is an impressive amount of evidence pointing to hepatic injury for duloxetine, the most important missing piece to support a box warning and second-line status is the absence of clean cases of death or transplant due to hepatic failure," Laughren said in his memo.

Many Patients Already Taking Cymbalta For Pain

It seemed agency staff wondered whether expanding the indication could create safety issues, particularly given the hepatotoxicity problem. Advisory Committee members will discuss the question. And Bob Rappaport, director, Division of Anesthesia and Analgesia Products, in his introduction to the briefing package asked committee members to remember that approval for chronic pain likely would mean a substantial increase in Cymbalta prescriptions.

But data from retail pharmacies compiled by the Office of Surveillance and Epidemiology also included in the briefing indicated an estimated two-thirds of Cymbalta use already is for an off-label diagnosis, including nearly 14 percent for pain conditions.

"Approving the use of Cymbalta for chronic pain may increase the patient exposure and physician prescribing to an area that is already not uncommon," OSE said in the documents.

A Different Burden Of Proof

The expanded indication has a difficult time at FDA; Lilly withdrew the application in 2008 after statistical concerns surfaced, and the advisory committee originally scheduled for January was cancelled (Also see "Cymbalta Advisory Committee Review In Chronic Pain Now Set For August" - Pink Sheet, 6 July, 2010.). The estimated user fee deadline for the application of April 3 passed with no action.

The revised application that Lilly submitted last year contains more recent studies in osteoarthritis pain and chronic lower back pain that were not contained in the 2008 submission. Evidence in those two conditions, as well as the previously demonstrated effectiveness in fibromyalgia and diabetic peripheral neuropathy, forms the basis for the chronic pain claim.

Despite the new trials, statistical problems may still come up during the committee meeting. FDA indicated the method Lilly used to analyze the new studies was not the appropriate way to handle missing data, and the advisory committee could provide an early read on how the agency will implement its emerging standards in that area (Also see "Industry, FDA Face Changes In Handling Of Missing Clinical Trial Data" - Pink Sheet, 16 August, 2010.). But FDA's analyses still found the drug was superior to placebo in reducing pain intensity in some of the trials.

FDA also indicated the burden of proof on Cymbalta may be different because it is not a typical drug used in chronic pain.

"For drugs that are not 'traditional analgesics,' such as duloxetine, where the mechanism of action for analgesia is not well defined, or for new molecular entities without any historic use in the treatment of pain, the weight of evidence required for a chronic or general pain indication may be greater than for drugs such as opioids and NSAIDs, where the mechanisms of action are well-defined and there is extensive use of these drugs for a multitude of painful conditions," the agency said in the briefing documents.

The agency said in the documents that it traditionally requires studies showing efficacy in each chronic pain category in order to obtain a general chronic pain indication, and Cymbalta was tested in enough populations to support the broadened indication.

-Derrick Gingery (d.gingery@elsevier.com)

Cymbalta Pain Advisory Committee Could Hinge On Hepatotoxicity Warning

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