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7:14 PM
Dec 07, 2018
 |  BioCentury  |  Regulation

Path to opioid-free pain relief

How clarity on outcomes could spur development of non-opioid analgesics

To jump-start development of analgesics that can help stem the opioid crisis, companies want FDA’s upcoming guidelines to reduce uncertainty around outcomes that constitute clinically meaningful opioid sparing. But while an advisory panel put some basic parameters around the idea, it did little to help FDA whittle down the possibilities for opioid-sparing metrics.

On Nov. 15, FDA held a meeting of the Anesthetic and Analgesic Drug Products Advisory Committee to discuss opioid-sparing outcomes for acute pain trials. Up for debate were the merits of various outcomes related to opioid sparing and the data needed to support them.

Takeaways from the meeting will inform four guidance documents FDA is drafting to foster development of non-addictive analgesics. In an Aug. 29 announcement, Commissioner Scott Gottlieb said the agency would release the documents in six to 12 months.

The first guidance will cover opioid-sparing drugs in acute pain. The other three will address risk-benefit analyses for new opioid analgesics, extended-release local anesthetics as alternatives to oral opioids, and non-opioid analgesics for chronic pain.

While half a dozen analgesics have gotten data included on their labels showing they reduce opioid use, the data don’t set a precedent for other companies because the majority of these labels explicitly state that the clinical meaningfulness of the findings is not known (see “Table: Opioid-Sparing Language in Drug Labels”).

Table: Opioid-sparing language in drug labels

FDA has approved at least six products with labels that include data on opioid-sparing activity, but none of the labels make clear the clinical impact of the findings. Moreover, several explicitly state that the clinical relevance of the decreased opioid use has not been demonstrated, which has kept these products from serving as regulatory precedents for new opioid-sparing therapies. None of the products’ trials measured opioid sparing as a primary endpoint.

Only one incorporated effects on opioid use in its clinical endpoint. Orilissa elagolix from AbbVie Inc. (NYSE:ABBV) was approved to treat moderate to severe endometriosis pain based on two trials with primary endpoints determined by a responder analysis that required both reduction in pain and no more than 15% increase in rescue pain treatment with NSAIDs or opioids.

The label for Orilissa, a GnRH/LHRH receptor antagonist, contains data describing reductions in both the absolute quantity of opioid used by the treatment groups and the proportion of opioid-free patients at 48 or 72 hours after surgery. The label for Exparel bupivacaine, an extended-release liposomal formulation from Pacira Pharmaceuticals Inc. (NASDAQ:PCRX), contains similar language.

Three other products’ labels also describe reductions in the amount of opioid used by the treatment groups in acute postoperative pain trials.

Prostate cancer drug Zytiga abiraterone from Johnson & Johnson (NYSE:JNJ) has a label that describes increased time to opiate use. Zytiga is an inhibitor of cytochrome P450 17 α-hydroxylase/C17,20 lyase (CYP17; CYP17A). Source: Drug labels, FDA briefing documents

CompanyProductIndicationOpioid-sparing labeling
Bristol-Myers Squibb Co. (NYSE:BMY) / Mallinckrodt plc (NYSE:MNK)Ofirmev acetaminophen injectionMild to moderate pain; moderate to severe pain with adjunctive opioid analgesics"There was an attendant decrease in opioid consumption, the clinical benefit of which was not demonstrated."
Cumberland Pharmaceuticals Inc. (NASDAQ:CPIX)Caldolor ibuprofen injectionMild to moderate pain; moderate to severe pain with adjunctive opioid analgesics"Efficacy was demonstrated as a statistically significant greater reduction in the mean morphine consumption through 24 hours in patients who received Caldolor as compared to those receiving placebo (47 mg and 56 mg, respectively)."

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