Vantage Point – Political backing unlikely to help developers of tamper-resistant painkillers

Pfizer’s decision to end development of three tamper-resistant opioid painkillers licensed from Acura Pharmaceuticals is the latest signal from a moribund area of drug development.

Efforts by numerous companies over the past few years to persuade the FDA to sanction abuse-resistant claims for various products have largely failed. However, opioid abuse remains a huge problem in the US and the political will to address the issue is clear – only two months ago a bill was proposed to Congress designed to encourage the development and uptake of tamper-resist technology. Should it pass the bill would help ensure that any formulation that made it to market with abuse-resistant claims would be hugely lucrative. But with the FDA showing no sign of capitulating on its stringent standards, decisions like Pfizer’s are understandable.

Halfway there

Drugs employing tamper-resistant technologies include Purdue’s extended-release form of oxycodone, OxyContin, Endo’s extended-release oxymorphone, Opana ER, and Acura’s oxycodone pill Oxecta, to which Pfizer has retained rights. Though these drugs are sold in the US, the FDA refused to accept that they are truly tamper resistant and all carry boxed warnings on their prescribing information stating that they are as open to abuse as other opioid agonists.

Despite the lack of firm marketing claims, it seems likely that the tamper-resistant attributes of these pills are working. Both Purdue and now Endo have seen franchise sales decline following the release of the new harder-to-abuse formulations; analysts have ascribed this in part to fewer prescriptions being written for abusers.

The FDA’s requirements for abuse-resistant formulations are certainly stringent and despite a lack of endorsement by the agency these drugs are widely considered to be harder to abuse. Submissions for OxyContin and Remoxy tested the formulations’ resistance to tablet fractionation, extraction, dissolution in ethanol, extraction in advanced solvents, injectability after vaporisation, advanced extraction, and liquid phase extraction.

The developers felt that the results of these tests were good enough to justify approval as tamper-resistant drugs; the FDA disagreed.

Attempts to enter

Pfizer has sought to enter this space via a number of routes, without success so far. It gained Remoxy through its acquisition of King Pharmaceuticals in 2010, a formulation of oxycodone licensed originally from Pain Therapeutics and employing technology designed by Durect. However the drug has been knocked back twice by FDA, the last time in June last year, and Pfizer appears to be dragging its feet over a refile. In a conference call on July 31, Geno Germano, Pfizer’s president and general manager of specialty care and oncology, said that the firm was hoping to meet with the FDA in the fourth quarter of 2012 to discuss the drug’s future, and was “cautiously optimistic” about bringing Remoxy to market.

Ongoing trials with another tamper-resistant product could explain the company’s reticence. ALO-02 is an extended release oxycodone/naltrexone co-formulation also acquired with King, but on which Pfizer would owe no royalties. One phase III trial has completed and one is due to report next year, according to clinicaltrials.gov.

Should Remoxy be presented to the FDA once again, the agency's verdict will be the next test of its willingness to grant a product abuse-resistance claims. There are few signs that it will capitulate.

And with a wholly owned product in development, if the answer is once again no Pfizer could well return the rights to this drug as well.

Political will

Abuse of prescription drugs is a huge public health problem in the US; the CDC estimates that one person dies every 19 minutes seeking a high.

US politicians have made their enthusiasm for tamper-resistant painkillers very clear. In June, the Stop Tampering of Prescription Pills Act 2012 was introduced to Congress. The bill seeks to define tamper-resistant drugs as oral opioids with physicochemical properties which “make manipulation significantly more difficult or ineffective” compared with standard drugs, or containing ingredients intended to deter abuse through “proven pharmacological effects”.

If passed in its current form, the STOPP Act would make it law that all new opioids, including generics, seeking FDA approval must contain tamper-resistant features. It would also force non tamper-resistant versions off the market the instant an abuse-resistant formulation was approved. Analysts at Jeffries wrote in a note this month that it is hard to predict the bill’s chances of becoming law, but that it appears to be “gaining traction”.

Companies are obviously in favour of the bill, and not only because it applies significant pressure to the FDA to approve stronger label claims. Its passage would also make life harder for generic companies, benefitting patent protected drugs should any manage to win the agency's backing.

Peter Clemens, Acura’s senior vice-president and chief finance officer, says that the new law would allow a broader definition of what constitutes tamper resistance: “To some extent the regulatory authorities here are holding companies to a standard of ‘abuse-proof’, and no company can meet that standard because there are no clinical trials for an illegal activity.”

He says that the agency should grant approval if a formulation can be shown to deter most abusers, rather than making abuse impossible.

“I think they’re asking almost the impossible. Changing the standard from abuse-proof to tamper-resistant is significant,” he says.

Mr Clemens agrees that it is hard to say whether the bill will pass, though the fact that it has bipartisan support is an advantage. “Drug abuse is an issue that cuts across both parties. It’s a societal issue that everyone recognises.”

Caution remains

The implications of such a bill, should it be passed, mean the FDA would still tread very carefully.

“Regulatory authorities will continue to be very sensitive,” Robert Hazlett, a research analyst at Roth Capital, says. “They don’t want to endorse a product as abuse-resistant and have people flock to it, and then all of a sudden somebody finds a way around it – they’d have a huge problem on their hands.

“So I think that the bar will continue to be massively high and I’m not sure that any company will ever get that claim.”

Consequently, the STOPP Act may achieve the opposite of what is intended: it may make the FDA even more cautious about affording a product abuse-resistant status, which would not help incentivise the development of new formulations.

Any opioid painkiller backed by the FDA as abuse-resistant after passage of the STOPP Act would be a very valuable asset. But with passage of the legislation uncertain and the FDA unlikely to lower its bar, companies hoping to compete in this area will face Olympic-size hurdles for years to come.

To contact the writer of this story email Elizabeth Cairns in London at [email protected]