FDA Grants PROP Petition (in Part), Proposes New Labeling and Requires Post-Marketing Studies for ER/LA Opioid Analgesics

By Delia A. Stubbs –

As previously reported, the Physicians for Responsible Opioid Prescribing (“PROP”) filed a Citizen Petition in March requesting that FDA limit the labeling of “controlled release” opioids to severe-only pain in non-cancer patients.  The petition also requested that FDA impose certain quantity and day limits on those medications.

After over 1900 comments on the petition were posted, including a rare endorsement by DEA, FDA issued its response last week (“PROP Petition Response”).  (FDA also responded to another similar petition, here).  Therein, FDA granted and rejected in part PROP’s requests.  FDA agreed to propose changes to the approved labeling of all Extended-Release/Long-Acting (“ER/LA”) opioid analgesics, but rejected PROP’s request for quantity and day limits.  It also rejected PROP’s request that the labeling changes be limited to “non-cancer” pain.

In sum, FDA’s proposal, which it issued pursuant to its authority under Section 505(o) of the Federal Food, Drug, and Cosmetic Act (“FDCA”), requests that all ER/LA opioid application holders, including NDA, BLA, and ANDA holders, modify those products’ labels as follows:

• Change the indication to “the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate.”  This change deletes the reference to moderate pain and adds the requirement to rule out other treatment options.  FDA explained that the change is intended to encourage prescribing decisions based on an individualized assessment.  PROP Petition Response at 8.
• Add to the Limitations of Use section:  “Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, and because of the greater risks of overdose and death with extended-release opioid formulations, reserve [the product] for use in patients for whom alternative treatment options (e.g., non-opioid analgesics or immediate-release opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.”  Id.
• Change the boxed warning to include the risk of neonatal opioid withdrawal syndrome (NOWS) and to urge providers to asses and monitor the patient’s risk of abuse/misuse of the drug.

FDA’s full changes are captured in its letter to affected application holders (“FDA Letter”).

FDA explained its reasoning for imposing these changes on ER/LA opioid analgesics only.  FDA’s decision is based on data demonstrating that the risk associated with these medications is greater than it is for their immediate-release counterparts.  See PROP Petition Response at 7.

FDA rejected, however, PROP’s requests to impose quantity and day limits on these medications.  FDA stressed that it could not grant those requests based on the data submitted by PROP, noting, among other reasons, that “creating a maximum dose of 100 mg MED, or another dose ceiling, could imply a superior opioid safety profile under that set threshold, when there are no data to support such a conclusion.”  PROP Petition Response at 12. 

Likewise, pursuant to its authority under Section 505(o), FDA is requiring ER/LA opioid analgesic application holders to conduct post-marketing studies to evaluate, among other things, the impact of long-term use of these medications on misuse, abuse, hyperalgesia, addiction, overdose, and death.  Interestingly, the scope of the data requested by FDA extends beyond the mere physiological effects of these drugs to behavioral and social phenomena associated with their misuse and abuse.  For example, FDA is requesting that holders conduct “a study to define and validate ‘doctor/pharmacy shopping’ as outcomes suggestive of misuse, abuse and/or addiction” that will then be used to inform the design and analysis of a study providing “quantitative estimates” of their “serious risks.”  See FDA Letter at 3-4.  Currently, concerns regarding doctor/pharmacy shopping are addressed on a federal level through enforcement actions by DEA.  FDA stated it expects application holders to “work together” to complete the post-approval studies.  It set milestones for completion which range from 2014 to 2018. 

So, what impact will these changes have on industry?  From a law enforcement perspective, likely little-to-none.  DEA’s enforcement actions against physicians, pharmacists, and other registrants, are predicated on proof that controlled substances were prescribed for “illegitimate medical purposes,” and that determination is based on an interpretation of state law, which permits physicians to prescribe drugs for “off-label” purposes.  However, physician and pharmacy boards may more carefully scrutinize the prescribing and dispensing of medications for off-label purposes, and may consider the treatment recommendations provided in these products’ labeling, if revised as FDA intends, as instructive of the standard of care. 

The results of the post-marketing studies could also inform FDA’s decision-making regarding scheduling recommendations for these and other drugs with potential risks of abuse.  One potential outcome would be the obtainment of an acceptable measure of a substance’s abuse potential, which is a required finding for determining whether, and in which category, to schedule a drug (or other substance) for control by DEA.  In a recent advisory committee meeting regarding the up-scheduling of hydrocodone combination products, clear concerns arose regarding the lack of such an agreed upon standard.  See our previous post, here. 

Douglas Throckmorton, M.D., Deputy Director of Regulatory Programs in FDA’s Center for Drug Evaluation and Research, stated “[t]he new labeling requirements and other actions are intended to help prescribers and patients make better decisions about who benefits from the use of these medications.”  Some might welcome these changes as a substitute for enforcement actions targeted at removing that discretion.  See Larry Houck, AMA Tells Pharmacists: “Don’t Call Us We’ll Call You.”

In response to FDA’s action, all ER/LA opioid analgesic application holders must submit a prior-approval supplement with revised labeling consistent with FDA’s proposal, or a declination and a statement of reasons for the declination, by October 10, 2013.  FDA stated that it may, after discussions with stakeholders, issue an order directing these (or other) labeling changes.