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May 26, 2008
 |  BioCentury  |  Regulation

Entereg gets hospitalized

Entereg alvimopan from Adolor Corp. and GlaxoSmithKline plc, approved last week to treat postoperative ileus following bowel resection surgery, will be the first new molecular entity to reach the market with a risk evaluation and mitigation strategy, the risk management toolkit created by the FDA Amendments Act of 2007.

Senior FDA officials are acutely aware that the first cohort of REMS will set precedents. Extra scrutiny, from both drug safety officials and FDA's lawyers, slowed the Entereg review and was partly responsible for the agency missing the Feb. 10 PDUFA deadline by over three months, according to Adolor and FDA.

Entereg posed a conundrum for the agency. Adolor demonstrated efficacy and safety in ameliorating postoperative ileus (POI), a serious but not life-threatening condition that can be caused by opioid pain relievers that slow or inhibit gastrointestinal tract motility. At the same time, a very different dosing regimen in a different indication, opioid-induced bowel dysfunction (OBD), was associated with an increase in the risk of serious and fatal adverse events.

The safety signals in OBD prompted FDA to impose a hold on all clinical trials of the drug. Although cardiology experts told FDA at a January advisory committee meeting that it is not reasonable to extrapolate safety signals from the long-term OBD trial to short-term use of Entereg for POI, the agency lifted the hold for POI - but not for OBD - only on the day it approved the drug.

GlaxoSmithKline has scheduled a meeting with FDA next month to discuss lifting the hold on OBD trials. If the trials resume, regulators may learn if there really is a risk from long-term use of the drug that needs to be mitigated.

Even if short-term use of Entereg poses little risk, FDA expressed concern in briefing documents for the January meeting that unrestricted marketing could lead to long-term use off label.

The Entereg REMS exploits a very clear natural barrier - the hospital door - between the approved indication, POI, and the off-label uses of greatest concern. As POI occurs in the hospital and patients are not discharged until it is resolved, the REMS imposes restrictions intended to ensure the drug is dispensed and used only in hospitals where bowel resection surgeries are performed. Most patients who need relief from OBD are treated on an outpatient basis.

The Entereg REMS appears to do precisely what Congress intended in FDAAA: it makes Entereg available to patients who can benefit while preventing it from reaching patients whom it may harm.

It will take some time, however, to determine if...

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