The United States is caught in an epidemic of prescription-drug overuse and abuse, and federal enforcers are revving up forces
to counter illegal diversion of approved drugs. Nearly 7 million Americans abuse psychotherapeutic drugs, according to a survey
by the Department of Health and Human Services (HHS), and prescription drug abuse now exceeds that of cocaine and heroin.
Consequently, manufacturers of opioids and other painkillers, along with prescribers and drug distributors, face increased
scrutiny from the Drug Enforcement Administration (DEA) and other regulators seeking to monitor drug distribution and prescribing
A House Energy and Commerce subcommittee held hearings in April 2011 and again in March 2012 to examine how DEA is tracking
and preventing inappropriate prescription-drug use, the effectiveness of state prescription drug monitoring programs, and
how well manufacturers, distributors and pharmacists prevent illegal diversion. Subcommittee Chair Rep. Mary Bono Mack (R–CA),
has pressed for policies to aggressively curb access to painkillers and anxiety drugs more severely since the suicide of her
son related to oxycontin abuse.
Of the thousands of pharmaceuticals approved by FDA for US marketing, about 250 are regulated by the the Controlled Substances
Act of 1970 (CSA). Some 80 drugs with high abuse potential but important medical uses fall under schedule II, including sleep
aides, diet pills, antidepressants, psychiatric drugs and antihyperactive therapies, as well as painkillers. Another 150 drugs
have relatively low abuse potential and are in schedules III–V with minimal restrictions, while more than 130 schedule I drugs
are dangerous and not approved for any uses.
DEA and other federal and state agencies have responded to the sharp rise in abuse of opioids and other legal drugs as part
of the 2011 Prescription Drug Abuse Action Plan released last year by the White House Office of National Drug Control Policy.
DEA agents have been closing down illegal online pharmacy sites and rogue pain clinics, particularly in Florida, that dispense
thousands of prescriptions for pain medicines. A main DEA thrust is to target drug wholesalers and distributors that fail
to detect and halt diversion; DEA recently moved to shut down a Cardinal Health distribution facility and four pharmacies
in Florida allegedly for overlooking highly excessive oxycodone orders.
Recent legislation also authorizes more aggressive efforts to remove leftover prescription drugs from family medicine cabinets,
and DEA is holding another national "take-back" initiative this month, aiming to collect tons of expired or unwanted medicines
for proper incineration. Brand and generic-drug manufacturers support these efforts, but are wary of proposals from the state
of Washington and a California county that call for manufacturers to foot the bill for more extensive collection of leftover
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. NDA's 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.