SEEKING DEA APPROVAL
Another concern for industry is that added requirements for bringing schedule II therapies to market can delay patient access
to new drugs by six months or more. DEA also sets annual quotas on production of controlled drug substances, a factor that
may aggravate shortages of certain widely used drugs.
FDA assesses about one-third of new drug applications (NDAs) to see whether they warrant additional scheduling review by the
DEA, noted Douglas Throckmorton, deputy director of the Center for Drug Evaluation and Research (CDER), at a February 2012
seminar on controlled substance regulation sponsored by the Food and Drug Law Institute (FDLI). CDER's Controlled Substance
Staff (CSS) determines whether DEA should evaluate the product further, which can lead to a complex scheduling process after
FDA approves the NDA.
This DEA review, for example, delayed marketing 11 months after FDA approval in 2008 of Esai's sedation medication Lusedra
(fospropofol). GlaxoSmithKline had to wait nearly six months to market its new epilepsy drug Potiga (ezogabine), despite early
communication with DEA on the product's unique features. DEA scheduling "is a big black box for industry," observed Esai regulatory
policy executive Ginny Beakes-Read, with no timelines for its actions and recommendations.
FDA officials advise manufacturers to address scheduling issues early in drug development to facilitate the review process.
Sponsors need to characterize whether a drug produces positive psychoactive effects, such as sedation, euphoria and cognitive
distortion, explained CSS pharmacology team leader Silvia Calderon-Gutkind. NDAs should clearly identify abuse liability—
or its absence—through evaluation of chemical properties, pharmacological and pharmacokinetic characteristics and clinical
data relevant to abuse.
CDER is working to improve its internal assessment process for controlled substances and to negotiate a memorandum of understanding
with DEA to facilitate exchange of confidential information on new drugs earlier in the review process. FDA issued draft guidance
last year on how manufacturers should assess the abuse potential of new drugs, and advice on developing abuse-deterrent formulations
is expected this year.
Although there's great interest in abuse-resistant patches or capsules, so far none have emerged that are "truly effective,"
said Gary Boggs, executive assistant in DEA's Office of Diversion Control, at the FDLI meeting. Manufacturers look to add
antagonists or change formulations to improve resistance, but DEA wants data to show that it works and warrants "down-scheduling"
to a DEA category that carries less regulation of production quantities, physical security, prescribing, and distribution.
Ultimately, better science may establish a clearer roadmap for assessing drug pharmacology and clinical studies related to
abuse issues, particularly for new drugs with novel mechanisms of action. Criteria for identifying and reporting adverse events
related to prescription-drug abuse also could provide safety data that supports changes in controls, as would efforts to increase
prescriber and patient education on the appropriate use of opioids and abused drugs.