Opioid Regulation Challenges FDA and Manufacturers

Published on: 
BioPharm International, BioPharm International-12-01-2013, Volume 26, Issue 12
Pages: 40–45

New policies and products seek to maintain access to pain medicines while curbing rampant abuse.

The escalating misuse of long-acting opioids has prompted efforts to formulate safer therapies for patients suffering from pain while also taking steps to limit inappropriate prescribing and illegal use. FDA recently agreed to tighter controls on widely used combination hydrocodone therapies (1). The agency earlier called for labeling changes on long-acting opioids to heighten awareness of risks and to limit prescribing (2).

FDA also is encouraging the development of abuse-resistant opioid formulations, as seen in guidance issued earlier this year on testing such products. Difficulties in bringing safer treatments to market, however, also prompted FDA to approve a new pure hydrocodone drug for extended relief of chronic pain, despite its potential for abuse. Agency officials explained that they could not block all new painkillers from the market while waiting for further development of abuse-limiting technology. These events illustrate the continual juggling act required of regulatory authorities and manufacturers to address the serious consequences of illegal opioid use while providing needed treatment for prescribers and patients.

Tighter controls


The pressure on FDA to do more to limit prescription drug abuse was apparent in its decision to support tighter controls by the Drug Enforcement Agency (DEA) for opioid treatments that combine hydrocodone with over-the-counter analgesics such as ibuprofen or acetaminophen. These widely used painkillers, including AbbVie’s Vicodin and UCB’s Lortab, have benefitted for years by being listed on DEA Schedule III controls. Drugs in that category are easier for doctors to prescribe, for patients to obtain, and for pharmacists to store and dispense. Schedule III status was supported by FDA based on its understanding that combination products are not as dangerous as full-strength opioids.

For the past decade, DEA has sought to change the schedule of these combination drugs to the more restrictive category as evidence mounted that abusers could manipulate extended-release products to achieve immediate “highs.” In 2008, FDA rejected DEA’s first request for this change, partly in response to loud objections from pharmacists, dentists and cancer and pain specialists as well as manufacturers. But as the medical community and public health authorities continued to campaign for stronger curbs, DEA revived its request in 2009 to FDA for support in changing the schedule for these drugs, providing added evidence on the dangers of these pain medicines.

Senator Joe Manchin (D-W. Va.) pressed to include the proposed scheduling change for combination opioids in the FDA Safety and Innovation Act (FDASIA). He backed down due to opposition from political and interest groups, but won a promise that FDA would re-examine the issue more thoroughly. FDA held a public meeting on opioid use in January 2013, where mounting evidence of the harm from abuse and misuse convinced an expert panel to support tighter controls on these medicines.

Janet Woodcock, director of the Center for Drug Evaluation and Research (CDER), announced in October 2013 that by year-end the agency would send DEA a formal recommendation to move hydrocodone combination products from Schedule III to Schedule II, a process that should be completed next year (1). The change will restrict prescriptions to 90 days from 180 days and require patients to bring a prescription to the pharmacy, instead of the doctor calling it in. As with other Schedule II drugs such as oxycodone, morphine and fentanyl, the aim is to make it harder for patients to obtain multiple refills in a short time period and to tighten controls on the storage and handling of these drugs by pharmacists.

Seeking more options
At the same time, the desire to ensure patient access to effective pain therapy prompted a surprise decision by FDA to approve a new, high-strength long-acting opioid medicine with no anti-abuse features (3). San Diego-based Zogenix had been seeking market approval for Zohydro ER (hydrocodone bitartrate extended release) for several years, but ran into objections related to product safety. An advisory committee in December 2012 voted against approval on the basis that the drug is dangerous and lacks abuse-deterrent features. Agency officials, however, overrode the committee decision.

The new drug automatically falls into DEA Schedule II, which means that it can be marketed immediately and avoid the often-long wait for DEA to determine appropriate controls. But prescribing will be restricted, and Zohydro will be subject to the Risk Evaluation and Mitigation Strategy (REMS) adopted in 2012 for all long-acting opioids.In addition, Zohydro has to carry new labeling that FDA announced in September 2013 for all extended-release and long-acting opioid drugs such as Perdue Pharma’s OxyContin (oxycodone) and Endo’s Opana ER (oxymorphone) (2). The new labeling advises physicians to prescribe these medications to treat only very serious, not moderate, pain as a way to limit use of these dangerous drugs.

Although FDA unveiled the labeling update with great fanfare, the new policy is not likely to have a big impact on opioid abuse. Boxed warnings and added risk information seem unlikely to curb inappropriate prescribing or to dissuade addicts from breaking the law. And the added postmarketing studies required by FDA are complicated and costly and may be difficult for manufacturers to carry out.

FDA’s approval of Zohydro was surprising because the product lacks features designed to deter abuse. FDA issued draft guidance in January 2013 advising manufacturers on strategies for testing drugs with anti-abuse features (4). And in April 2013, FDA approved new labeling that allows promotion of abuse-deterrent features of Purdue’s reformulated OxyContin. Evidence that the product may impede abuse, moreover, prompted FDA to declare that it would not approve any generic versions of the original OxyContin formulation, no longer produced by Purdue Pharma (5).

The complexities of the regulatory status of these pain medicines, though, is seen in FDA’s contrary decision a month later, when it decided not to grant that same kind of protection from generic competition for Endo Pharmaceutical’s reformulated Opana ER. FDA concluded that despite formulation changes, the drug remained vulnerable to abuse and could be prepared for injection and snorting.

Approaches for developing and testing abuse-resistant features on drugs were discussed further at a scientific meeting Sept. 30-Oct. 1, 2013 organized by the Cross-Company Abuse Liability Consortium and the College on Problems of Drug Dependence. Scientists from industry, academia, and FDA examined preclinical and postmarketing study approaches for demonstrating the potential for abuse prevention. FDA particularly wants to encourage the development of generic drugs with anti-abuse formulations to facilitate patient access to safer, less costly therapies.  

Experts at the meeting acknowledged that technology supporting abuse deterrence is still new and untested, and that much work is needed on methods for analyzing clinical data on abuse and the impact of new formulations on rates of abuse. FDA officials and pharmaceutical companies will continue to seek more understanding on what types of approaches can provide meaningful abuse deterrence as part of its effort to provide patients with safer, effective pain therapies.

1. FDA, “Statement on Proposed Hydrocodone Reclassification from Janet Woodcock, M.D., Director, Center for Drug Evaluation and Research,” Oct. 24, 2013.
2. FDA, “FDA Announces Safety Labeling Changes And Postmarket Study Requirements For Extended-Release And Long-Acting Opioid Analgesics,” press release (Sept. 10, 2013).
3. FDA, “FDA Approves Extended-Release, Single-Entity Hydrocodone Product,” Press Release (Oct. 25, 2013).
4. FDA, Draft Guidance, Abuse-Deterrent Opioids--Evaluation and Labeling (Silver Spring, MD, January 2013).
5. FDA, “FDA Approves Abuse-Deterrent Labeling For Reformulated OxyContin,” press release, (Apr. 16, 2013). 

Jill Wechsler is

BioPharm International’s

Washington editor, Chevy Chase, MD, 301.656.4634,

[email protected]

Read Jill’s blogs at PharmTech.com/wechsler.