Opioid class REMS will not delay new drug approvals, FDA says
This article was originally published in Scrip
Ongoing deliberations over a single risk evaluation and mitigation strategy (REMS) for long-acting and sustained-release opioids will not block approval of new drugs within the class, US FDA office of new drugs director Dr John Jenkins said.
Speaking to reporters after a two-day meeting on proposed REMS elements for the opioid class, Dr Jenkins said the agency sees "a path forward" for approving long-acting opioid agents that are purported to be less susceptible to abuse or tampering than currently available products, even though it may be months or years before a classwide REMS is in place.
"We do feel that we have a path forward that would allow the possibility for new products in this class to be approved before the final class REMS is put into place, and there are individual details that need to be worked out that apply to each and every one of those applications," Dr Jenkins said. "Even having said that, we still have to work through making sure that they're coming to market with at least the same risk management efforts that already exist for the existing products."
pipeline
The FDA is requiring manufacturers of most long-acting and sustained-release opioids and immediate-release methadone to develop a single, classwide REMS to reduce deaths and serious injuries resulting from misuse, abuse and overdose of the drugs.
At least three applications have come before the FDA in the past year for reformulated sustained-release opioids that are purported to be less prone to abuse or diversion and would presumably be encompassed by the classwide REMS. Each application has had its own problems or deficiencies and none has been approved to date. FDA officials have been reluctant to allow a product to claim it has abuse deterrent properties absent clear clinical proof of reduced abuse.
In November the FDA's anaesthetic and life support drugs and drug safety/risk management committees reviewed two drugs: King Pharmaceuticals' (formerly Alpharma) Embeda, a modified-release formulation of morphine coupled with the opioid antagonist naltrexone; and Pain Therapeutics/King's Remoxy, a controlled-release form of oxycodone.
The panel said Embeda provided an incremental improvement over existing controlled-release morphine products because it appeared to be less susceptible to abuse and misuse, but more data were needed on potential abuse by intravenous injection, snorting and chewing. The late December user fee date passed without FDA action. In its most recent quarterly filing with the Securities & Exchange Commission, King said it expects FDA approval of Embeda this year.
The panel majority said Remoxy appeared to be less susceptible to abuse and misuse than Purdue Pharma's OxyContin (oxycodone extended-release), but many members expressed concerns about the oral opioid's safety when injected or inhaled. They also said the drug should be studied in addicts to gauge whether it results in less abuse or if this population could defeat the formulation's controlled-release properties. The FDA issued a complete response letter on Remoxy in December seeking additional non-clinical data, and King said it expects to meet with the agency in July.
In May 2008, the FDA's experts said Purdue's proposed reformulation of OxyContin was unlikely to reduce abuse or diversion and should not be marketed without further data.
The agency, acting on the advice of its outside experts, also issued a complete response letter last year rejecting a non-cancer pain indication for Cephalon's Fentora (buccal fentanyl), instead directing the company to first strengthen its current risk management programme for the opioid.
In December, Acura Pharmaceuticals submitted an NDA for Acurox, an immediate-release oxycodone plus niacin formulation that is purported to have abuse deterrent properties. The product, which is being developed in conjunction with King, has a June 30th user fee date. Neither buccal fentanyl nor immediate-release opioids are part of the FDA's proposal for a classwide REMS.
immediate release
During the public meeting some speakers requested that immediate-release formulations also be included in the classwide REMS for long-acting opioids. Speakers said both types of products are part of the same problem of misuse and abuse, and REMS elements that impose prescribing restrictions on long-acting opioids might could shift more patients to immediate-release formulations.
The FDA said the initial focus has been on long-acting products because they have caused serious problems, including overdose and death, resulting from too frequent dosing or dose-dumping when sustained-release mechanisms are defeated. The request to include immediate-release formulations in the REMS is "something we'll have to think about, keeping in mind that we have to meet the statutory requirements for when a REMS programme is warranted and can be invoked, so we'll have to go back and reconsider whether we want to expand or stick with the long-acting and sustained-release products", the FDA's Dr Jenkins said.
Including immediate-release formulations would greatly expand a REMS that already is complicated by the large size of the prescribing base and magnitude of patient use. About 26 million US prescriptions for long-acting opioids were written last year by a total of 375,000 doctors, compared with about 200 million annual prescriptions for the entire opioid class, according to data presented at the meeting.
The long-acting opioid REMS programme would be the largest, most complex risk management programme ever implemented in the US. One REMS consultant who testified at the meeting predicted it would take at least a year to get such a programme up and running.
Dr Jenkins said the agency may look for risk management measures that can be implemented in the interim while a full-scale REMS is being developed. "I think one of our goals when we go back and regroup and start thinking about what we've heard is, are there short-term deliverables, even independent of a required risk evaluation and mitigation strategy, that we can undertake to try to start having an impact now versus waiting until the ultimate REMS letter is signed and says you're approved and you have to go put this into place?"