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