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A Lack Of Data Keeps Propoxyphene On The Market ... For Now At Least

Executive Summary

The lack of clear data substantiating the risk of fatal overdose with propoxyphene-containing drug products seems to have led FDA to its decision to keep the products on the market - and thus deny Public Citizen's petition for their withdrawal

The lack of clear data substantiating the risk of fatal overdose with propoxyphene-containing drug products seems to have led FDA to its decision to keep the products on the market - and thus deny Public Citizen's petition for their withdrawal.

FDA's recent action against propoxyphene-containing products shines a light on a curious scenario: the drugs lack meaningful data for both their efficacy and their risk, and in a game of catch-up - the drugs were approved in the 1950s before efficacy standards were developed - the agency now is calling for a number of different trials to be conducted. Those trials are aimed at refining FDA's understanding of how propoxyphene products are used in the market and gaining better real-world information on their safety profile.

On July 7, FDA announced that in an effort to preserve pain medication options for patients, it would not remove propoxyphene-containing products from the market (Also see "FDA Takes Action Against Propoxyphene But Keeps It On The Market" - Pink Sheet, 7 Jul, 2009.). It chose instead to rely on its arsenal of risk management tools to address the risk of potentially fatal overdose.

But in addition to a labeling change in the form of a boxed warning emphasizing potential for an overdose and a Medication Guide, which automatically triggered the development of a Risk Evaluation and Mitigation Strategy, the agency also is invoking its Food and Drug Administration Amendments Act authority to require manufacturers to conduct a new safety study and is working with other agencies to conduct additional studies, which could result in a withdrawal later on.

FDA's decision seems to go against the prevailing winds. In considering the propoxyphene issue at a Jan. 30, 2009, meeting, FDA's Anesthetic and Life Support Drugs and Drug Safety and Risk Management advisory committees voted to remove the drug from the market, despite the fact that there would be complications with its removal (Also see "Public Citizen Takes On Propoxyphene Again, This Time Comes Out On Top" - Pink Sheet, 9 Feb, 2009.).

In addition, the EMEA recommended June 25, 2009, that member states gradually withdraw propoxyphene-containing products from their markets.

But without clear evidence in hand, it would have been difficult for FDA to withdraw the products from the market. The agency's denial of the Public Citizen petition makes clear how flawed the datasets on the propoxyphene risks were.

Addressing Petition Unveils Dearth Of Data

Despite the fact that safety issues have been lingering with propoxyphene since the drug was first approved (see chart: " Propoxyphene's Tumultuous Timeline: Always Avoiding the Worst "), it was not realized how little information was there until Public Citizen sued the FDA for not responding to a petition filed some years ago requesting that propoxyphene-containing products be phased out of the market due to their inefficacy and risk.

Specifically, Public Citizen argued for a phased withdrawal due to the drug's high level of cardiotoxicity; the substantial number of deaths, both accidental and intentional, associated with the drug; its over-prescription in elderly populations; its addiction-causing properties; and its overall ineffectiveness as pain medication.

But FDA, in announcing its actions against the drug, also denied Public Citizen's petition, saying that while it agrees that in propoxyphene overdoses there is evidence of cardiac effects, it disagrees with Public Citizen's claim that the drug is cardiotoxic when used as directed, including in the elderly.

FDA's response to Public Citizen's petition highlights just how patchy the available propoxyphene data are.

Holes In Studies And Databases

Public Citizen backed its petition using the Drug Abuse Warning Network data, the Adverse Event Reporting System, medical examiner data from Florida, FDA's original efficacy review for propoxyphene, data from the EU, and possible treatment alternatives to the drug - FDA found holes in all of these sources.

The data Public Citizen used to support the specific claim of causing cardiac effects when used as directed, for example, was based on a table of clinical and anecdotal data from both published and unpublished sources, which FDA says does not hold water. "In addition, we do not find the one peer reviewed paper referenced in the table persuasive, and our independent review of the literature revealed a dearth of scientifically sound evidence to support an association between propoxyphene and cardiotoxicity," FDA's response states.

FDA also stressed that its review of AERS data, while suggesting a high enough level of metabolites during an overdose to become cardiotoxic, cannot be used to conclude a relationship between the drug and cardiac effects. Furthermore, the agency said, in its review of serious adverse events reported to AERS between 2006 and 2007, there was insufficient evidence to support any association between propoxyphene and cardiotoxicity.

Many of the reports, the agency noted, were heavily confounded by an underlying medical history of cardiac issues and the use of concomitant medications that could have led to the cardiac events reported.

FDA also took issue with the DAWN data used in Public Citizen's petition, noting that of the 3,154 total reports pertaining to propoxyphene alone in 2007, only 415 of those involved a cardiac event, most of which were not indicative of lethal cardiotoxicity.

Importantly, the agency continued, DAWN data show very few deaths related to propoxyphene products and fewer deaths associated with the use of propoxyphene products than with the use of the other opioids, including oxycodone, hydrocodone and methadone.

DAWN data, FDA warns in its response, must be used with great caution when seeking to detect a trend in deaths involving any drug over a lengthy period of time, including propoxyphene.

For example, from 1981 to 1999, trend analysis can be done only by identifying a consistent panel of medical examiners and coroners from metropolitan areas who submitted sufficient data to DAWN each year and comparing only those jurisdictions that remain within the consistent panel from year to year. Another problem with the system's reliability is that during those years, DAWN collected only data related to "drug abuse" deaths, whereas after 2003 DAWN expanded its data collection to include reports of all "drug-related" deaths, significantly increasing the scope of data collected.

Additional Flawed Data Sets

In response to Public Citizen's suicide claim, FDA said it has no reason to believe the withdrawal of propoxyphene products from the market will curb the incidence of intentional drug overdoses, particularly given the multitude and availability of other products on the market that can be substituted.

Supporting that statement, FDA noted that in the AERS database, the majority of the deaths reported involving propoxyphene products involved multiple other drugs. "The multifactorial causes of suicide, compounded by the fact that most self-poisonings involve multiple drugs, make it impossible to know whether withdrawing propoxyphene from the market would result in fewer completed suicides."

Public Citizen's claim that propoxyphene is over-prescribed to elderly populations was backed up by an article by Beers et al. that FDA noted did not use peer-reviewed scientific data, but rather opinions offered by geriatricians. The agency also stressed that because of the recently recognized hazard of NSAIDs, propoxyphene products are a useful alternative for some elderly patients who cannot tolerate NSAIDs.

Approval Based On Multiple Failed Trials

Under the Food, Drugs and Cosmetics Act, FDA can withdraw a product if new information, evaluated together with evidence available at the time the application was approved, shows a "lack of substantial evidence that the drug will have the effect it purports or it represented to have under the conditions of use prescribed, recommended or suggested in the labeling thereof."

Clinical trials of analgesic drugs generally rely on demonstrating superior efficacy to either placebo or other drug products with the same or similar indication.

FDA relied on data from seven clinical trials submitted during the original NDA for Darvon and Darvon-Compound. But only three of the seven trials - two in support of Darvon and one in support of the Darvon-Compound - demonstrated analgesic efficacy.

The agency stressed that even when using placebo as a comparator, drug products known to be effective analgesics still may fail to demonstrate efficacy in some clinical trials for a variety of reasons, including a choice of study population that is not well suited for the drug. In propoxyphene's case, FDA said, that was the problem.

Complicating the issue further, the clinical trials used to back up the drugs' first approvals differ considerably from modern clinical trials in that they are of shorter duration, are conducted in a single study site, and evaluate a single dose of the study drug. The statistical methods used to analyze the trial data also have improved considerably in the decades since the drugs were first approved.

Despite the lack of supportive studies, FDA said, "the data are sufficient to demonstrate that both propoxyphene and the combination propoxyphene/ acetaminophen are superior to placebo."

"Equally important," the agency continued, "FDA does not have new information to show a 'lack of substantial evidence' ... as required by the FDCA to initiate the withdrawal of a drug product."

Additional Trials May Bring New Data

But soon it may. The underwhelming amount of data available to both Public Citizen and FDA triggered the agency to include as part of the actions taken against the drug a requirement that Xanodyne - the only brand manufacturer of a propoxyphene product - conduct a study on propoxyphene's cardiac effects, particularly on the QT interval.

FDA also will work with the Centers for Medicaid and Medicare Services to study how often the elderly are prescribed propoxyphene instead of alternative pain relievers and with the Veterans Administration to access its patient database to evaluate any differences in the safety profile of propoxyphene compared to other drugs for pain. FDA's Office of Epidemiology is exploring the feasibility of studying propoxyphene with one or more of its contractors, such as Kaiser or Vanderbilt, and is examining the possibility of reviewing medical examiner data in DAWN.

During a media briefing, CDER's Office of Drugs director Janet Woodcock stressed that data FDA accumulates from the various safety studies could result in additional regulatory action.

- Lauren Smith ([email protected])


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