The FDA stirred up a hornet's nest with an unprecedented request to Endo International plc to remove voluntarily its opioid pain medication, a tamper-resistant reformulation of Opana ER (oxymorphone hydrochloride), from the market. The action came following a joint meeting in March of the agency's Drug Safety Risk Management and Anesthetic and Analgesic Drug Products Advisory Committees to review pre- and post-marketing data about the abuse of Opana ER, the product's overall risk-benefit profile and the abuse of generic oxymorphone ER and oxymorphone immediate-release products. The agency said that, "after careful consideration" it was seeking removal of the single product "based on its concern that the benefits of the drug may no longer outweigh its risks," confirming that the action represented its first attempt to remove a currently marketed opioid pain medication from sale "due to the public health consequences of abuse."

Endo's shares (NASDAQ:ENDP) took a sharp hit, closing at $11.49 for a decline of $2.29, or 16.6 percent, in heavy trading. Some analysts pointed to opportunities for safer opportunities in the pain space while others observed that revenues from Opana ER were already feeling the effects of generic products. In a head scratcher, however, generic products were excluded from the FDA's action, and "at this time, the FDA cannot speculate as to what action it may take in regard to other specific opioid products," FDA press officer Sarah Peddicord told BioWorld.

"As discussed at the public advisory committee meeting on Opana ER abuse in March 2017, the FDA is currently assessing the latest available data on abuse patterns for generic oxymorphone ER and oxymorphone IR products," she added. "We do not have further information to share at this time, and will keep the public informed on next steps from the agency, as appropriate."

According to the FDA's Orange Book, at least seven companies offer generics, of various strengths, that reference the original Opana ER. When Endo replaced the drug's original version with the tamper-resistant formulation, the company asked the FDA to remove the generics but the agency refused.

In a statement, FDA Commissioner Scott Gottlieb said the action was needed to confront the nation's opioid epidemic, which he called "a public health crisis" that required "all necessary steps to reduce the scope of opioid misuse and abuse."

He added, "We will continue to take regulatory steps when we see situations where an opioid product's risks outweigh its benefits, not only for its intended patient population but also in regard to its potential for misuse and abuse."

Despite bruising confirmation hearings in which Gottlieb's ties to the biopharma industry took center stage, he maintained all along that the opioid epidemic was his top priority, calling it "a staggering human tragedy."

Although Gottlieb maintained during the confirmation process that opioid problem has surpassed the FDA's ability to address it alone, he nevertheless maintained that the agency was in a position to establish a framework and provide guidance for the development of solutions such as nonopioid pain alternatives. He also stressed the need for a path to approve generic drug-device combination naloxone products to create competition, and lower prices, for emergency treatment of opioid overdoses. (See BioWorld Today, April 6, 2017.)

Gottlieb's emphasis on addressing opioid abuse as his top priority may have helped him sidestep an issue that temporarily stalled his predecessor's confirmation when Sen. Edward Markey (D-Mass.) placed a hold on the nomination of Robert Califf, demanding the FDA get tougher on its approval of opioid products. Markey opposed Gottlieb on the same grounds. (See BioWorld Today, Jan. 27, 2016, and Feb. 9, 2016.)

The FDA said its decision was based on a review of available post-marketing data on Opana ER, which it said showed a shift in the route of abuse from nasal to injection following the product's reformulation. In turn, injection abuse was associated with an outbreak of HIV and hepatitis C and cases of the blood disorder thrombotic microangiopathy.

The agency also pointed to the outcome of the March advisory committee (adcom) meeting, where members voted 18-8, with one abstention, that the benefits of reformulated Opana ER no longer outweighed the risks of keeping it on the market.

In a statement responding to the FDA's action, Dublin-based Endo pointed out that, despite the adcom vote, more than half of the members expressed a preference for keeping Opana ER on the market but with additional regulatory restrictions to mitigate risks of misuse and abuse.

FDA willing to force product off market

Opana ER was initially approved in 2006 to manage moderate-to-severe pain when a continuous, around-the-clock opioid analgesic was needed over an extended period. In 2012, Endo replaced the original formulation of Opana ER with a formulation designed to resist physical and chemical manipulation for abuse. The FDA determined the product continued to meet regulatory standards for approval but declined the company's request to include a label that described potentially abuse-deterrent properties. Following conversations with the agency, last year Endo withdrew its supplemental new drug application relating to the abuse-deterrent labeling without prejudice to re-filing while it continued to collect and analyze epidemiological data.

Should Endo fail to comply with the FDA's request to remove reformulated Opana ER from the market voluntarily, the agency said it will take steps to require the product's removal by withdrawing approval. No timetable was set, but the FDA said it is moving to alert health care providers about "the particularly serious risks associated with the abuse of this product."

In its statement, Endo said it is reviewing the FDA's request and is evaluating the full range of potential options to determine the appropriate path forward. The company pointed out that the request did not indicate uncertainty with the product's safety or efficacy when used as prescribed, citing its confidence "that Opana ER has a favorable risk-benefit profile when used as intended in appropriate patients."

For Endo, which is already feeling pressure from generics on Opana ER sales, the financial impact from product's removal could be "muted," suggested Canaccord Genuity analyst Dewey Steadman, who nevertheless lowered the company's price target to $12 from $14.

"Opana ER represented less than 5 percent of overall Endo revenue and around 10 cents in [earnings per share] each quarter following several quarters of decline due to generic competition on the original formulation [which will likely stay on the market] and a broad decrease in opioid prescribing over the past 18 months," Steadman wrote in a company note. He added, "We believe the optics of a challenge to FDA would be far worse than the reality of a modest decrease to short-term revenue, especially given heightened awareness of the opioid abuse epidemic."

Still, the FDA's request comes as a warning shot across the industry's bow, Steadman suggested, signaling "FDA may be willing to take increased interest in the active regulation of opioid products to curb prescribing habits." Products that use similar formulations, including those that may generate additional risks or adverse events, may come under scrutiny in the future, he added.

In his industry note, Piper Jaffray's David Amsellem acknowledged that "we were not surprised by the request given the outcome of the advisory committee meeting held this past March (and given the overall scrutiny of the opioid space)."

With Endo also facing pressure related to settlements over its vaginal mesh product, "we continue to find it difficult to envision a sustainable recovery in ENDP shares at least through 2017," Amsellem wrote.

He was more reticent to see a read-through to the industry as a whole, however, noting, "The FDA cited data regarding abuse of Opana ER via the injection route, something that was less of an issue with the original formulation. Put another way, the availability of this particular crush-resistant product created other abuse/diversion issues, and the confluence of that and the increased overall scrutiny of opioids in our view drove the FDA's action today."