With a number of issues about opioid drugs on the table, FDA has the opportunity to redefine the marketplace for those products, a redefinition that will clarify the path forward for generic products.

As it searches for a new paradigm for regulating use of the pain killing medications, the agency is juggling the need to limit abusers’ access to the drugs while maintaining access for pain patients.

One option suggested to the agency is to write labeling to restrict legal use of the drugs. A petition from Physicians for Responsible Opioid Prescribing calls on FDA to limit their use for non-cancer pain to those with severe pain at a maximum daily dose equivalent to 100 mg of morphine and continuous use for no more than 90 days Also see "Citizen Petition Seeks Limited Opioid Drug Indication To Curb Overuse And Abuse" - Pink Sheet, 6 August, 2012..

Supporters of that proposal insisted during a Feb. 7-8 FDA meeting that relabeling would not curtail access for those who need the drugs, but in fact would protect pain patients who often suffer the consequences of addiction and misuse.

Opioid Issues Pending At FDA

NDA for Zogenix Inc.’s single-entity hydrocodone product Zohydro, which has a user fee date of March 1
Separate petitions from Endo and Purdue seeking to eliminate their original formulations of Opana ER and OxyContin as reference products for ANDAs; FDA must respond to the Endo petition by May 10 but there is no deadline for a decision on the Purdue petition
Request by DEA to up-schedule hydrocodone combination products to Schedule II under the Controlled Substances Act
Petition from Physicians for Responsible Opioid Prescribing to narrow the non-cancer pain indication for opioids

FDA would impact the market in a big way if it opts to essentially require abuse-deterrent formulations to address the country’s drug addiction problems. That is the preference of some in the medical community. Lack of an abuse-deterrent formulation was one of the objections raised by the Anesthetic and Analgesic Drug Products Advisory Committee when it recommended 11-2 against approval of Zogenix Inc.’s Zohydro ER Also see "Opioid Abuse-Deterrent Formulations Could Become Prerequisite To Approval" - Pink Sheet, 17 December, 2012..

While FDA considers that option, the agency has issued draft guidance on how to obtain four different labeling claims related to a product’s ability to deter abuse ([A#00130114010]).

The guidance does not, however, say how the agency will handle generic drugs without abuse-deterrent properties. In correspondence to Congress sent the day before the draft guidance was released, FDA Commissioner Margaret Hamburg said that if new opioid formulations “significantly” deter abuse, generic versions will have to do so as well.

An important guidepost in that area will be the agency’s decisions on whether Endo Pharmaceuticals Inc.’s Opana ER (oxymorphone HCl) and Purdue Pharma LP’s OxyContin (oxycodone) will remain available as reference products.

Endo asked the agency in a citizen petition to declare that Opana was withdrawn from the market for safety reasons, making it ineligible as a reference product Also see "Endo Seeks To Block Generics Of Opana ER That Are Not Crush-Resistant" - Pink Sheet, 17 September, 2012.. In the case of OxyContin, similar citizen petitions from Lachman Consultant Services Inc. and the law firm Sheppard Mullin Richter & Hampton asked FDA to declare that Purdue’s voluntary withdrawal of the original formulation was for reasons other than safety or effectiveness Also see "Purdue Moves To Stave Off Branded, Generic Competitors To New OxyContin" - Pink Sheet, 14 February, 2011.. Those petitions made it unnecessary for Purdue to ask for clarification of the issue.

Because of a 270-day deadline set by the FDA Safety and Innovation Act for responding to discontinuation petitions, FDA has until May 10 to make a ruling on the Opana petition. A U.S. District Court judge in the District of Columbia in December dismissed an Endo suit seeking an earlier decision and FDA denial of ANDAs referencing the original Opana ([A#14121203008]).

The OxyContin petitions were filed before enactment of FDASIA so FDA has no deadline for a response. However, the main patent on the original OxyContin expires in April, so that could provide an impetus for a response to the request for clarification of the drug as a reference product.

Endo and Purdue have filed separate petitions asking FDA to require any generic that references their reformulated products to demonstrate similar abuse-resistant characteristics. Endo filed its petition in November. Purdue refilled a petition in August.

FDA has left it unclear as to whether it will require generic firms to make those demonstrations. In Jan. 23 responses to the companies on the similarity issue, FDA denied the petitions, saying it cannot decide on what will be required outside the context of an application and the review process.

Prior to those responses, there appeared to be lack of communication at the Office of Generic Drugs where a staff member responded to a suitability petition from Lannett Co. Inc. about an ANDA for a generic of the reformulated OxyContin with a question about whether there is evidence the proposed drug product is tamper-resistant. “If not, it will be deemed unable to meet the conditions of use of the RLD (which has been reformulated to be tamper-resistant) and therefore denied,” an email to the company from FDA.

But on Jan. 18, just five days before the Jan. 23 responses to Endo and Purdue, OGD Regulatory Support Branch Chief Martin Shimer clarified to Lannett that: “the agency has not yet established a policy regarding this issue, and the comment in the Dec. 5 e-mail is not an accurate statement of agency policy.”

Setting A Maximum Dose

The choice facing FDA regarding labeling of existing opioid products is more a public health balancing act than a scientific conundrum.

At the FDA public meeting, Hillary Kunins of the New York City Department of Health and Mental Hygiene presented data that the risk of overdose “increases with increased opioid doses.” The odds of overdose for those receiving more than 100 morphine milligram equivalents (mme) is two to 11 times greater than for those taking less than 20 mme, she said.

“A maximum dose of 100 mme would likely affect a minority of patients,” she added. The New York State Prescription Drug Monitoring Data program indicates that only 7% of New York City residents fill a prescription at that dose and these represent less than 2% of New Yorkers and include some prescriptions for cancer or end-of-life care, so “even fewer patients would be affected” if limits are not applied to those conditions, she said.

Limiting duration of use also would have limited effects on pain patients, she said, noting that only 7% of prescriptions in New York City are for 90 days or more of consecutive use.

Adding to the data on the adverse impact on pain patients caused by high doses of opioids, Tara Gomes, University of Toronto, reported that in Ontario, an individual prescribed >200 mme had a threefold increased risk of dying from opioid-related causes, and even those with a prescription for 50 mme to 200 mme had double the risk of dying of opioid-related causes compared to those receiving <20>

Kevin Nicholson of the National Association of Chain Drug Stores, however, cautioned that a maximum dose is an arbitrary standard and would affect the sickest patients the most. It could lead to off-label prescribing that would affect reimbursement, he noted.

Kunins suggested that insurers were unlikely to discontinue reimbursement. But, she noted, “FDA’s charge is to aggregate public health benefit of a product compared to its evolving risk profile and not to set payment policy.”

A difficulty for FDA is the lack of data on whether physician education and other programs designed to reduce drug abuse actually work (see related story,[A#00130218012]).

FDA’s Opioid To-Do List Could Redefine Pain Market For Brands, Generics

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