The proper use of prescription drugs is central to a number of important regulatory and public policies issues now in the spotlight.
The proper use of prescription drugs is central to a number of important regulatory and public policies issues now in the spotlight. The White House is orchestrating a campaign to reduce abuse and misuse of prescription drugs, with a focus on extended-release opioids. The spread of adulterated drugs across the globe is prompting initiatives to curb violative imports. At the same time, patient groups and physicians are pressing to resolve shortages of important therapies and to ensure access to needed medicines-a goal that raises challenges for FDA as it strives to address these issues.
SHORTAGES AND SUPPLIES
From high-security prisons to cancer clinics, critical drug shortages are focusing attention on drug supply issues. Disruptions in access to life-saving chemotherapies, anesthetics and pain medications have made headlines, along with difficulties for law enforcement officials seeking approved drugs for lethal injection. Many of the shortages involve generic sterile injectibles that have been hit by a number of problems: industry consolidation that reduces competitive production, limited supplies of active ingredients, and manufacturing problems that have led to plant closures.
In response, FDA has moved to quickly approve the import of cancer and leukemia therapies produced overseas. The agency also has authorized prison officials to import sodium thiopental from unapproved foreign producers, a move that generated lawsuits arguing a lack of evidence for potency and efficacy of the imported drug, along with opposition from foreign governments opposed to capital punishment.
The situation has prompted calls for FDA to gain authority to require advance notice from more manufacturers about plans to discontinue production of short-supply drugs. The agency has fairly limited notification authority and often receives scant information from manufacturers on factors causing new shortages. Pharmaceutical companies generally oppose long advance notification requirements, noting that supply changes often cannot be predicted far in advance, and that manufacturing problems usually occur without warning.
While some FDA offices seek to accelerate access to vital medicines made abroad, agency field inspectors are struggling to monitor a surge in imports of food and medical products. FDA has been working for more than five years to install the automated PREDICT (Predictive Risk-based Evaluation for Dynamic Import Compliance Targeting) computer system to replace its outdated import screening process that cannot cope with some 24 million shipments arriving at US ports of entry this year. The import volume includes up to 40% of drug products and 80% of active pharmaceutical ingredients.
The new system aims to prevent future heparin crises by shifting from inspecting imports at point of entry, to ensuring that drugs meet quality standards where they are produced, explained FDA Commissioner Margaret Hamburg at an April hearing before the House Energy and Commerce Committee. FDA critics complained that PREDICT is deployed in only 4 of 20 FDA district offices and pressed Hamburg to do a better job. The commissioner blamed delays on software problems and noted that PREDICT was being expanded from California, Seattle, and New York to field offices in Florida and San Juan, Puerto Rico, bringing coverage up to 50% of all imports this year.
FDA would gain more tools for managing imports, moreover, with proposed drug safety legislation that authorizes the agency to detain and destroy violative imports; to impose stiffer criminal and civil penalties on rule-breaking suppliers; and to refuse admission to products from plants that block FDA inspections. A bill sponsored by Rep. John Dingell (D-Mich.) also would give FDA authority to issue subpoenas related to drugs, as with recently approved food safety legislation, and would authorize more FDA overseas inspections, recalls of tainted products and collection of more manufacturing information.
CRACK DOWN ON OPIATES
At home, the most alarming drug safety issue involves overuse, misuse and abuse of extended-release opioid drugs, a problem that has prompted FDA and manufacturers to devise a Risk Evaluation and Mitigation Strategy (REMS) to promote safe use of these medications. The task has been in the works since 2009, but is complicated because millions of patients use these drugs to relieve acute pain.
Yet, prescription drug abuse has become the nation's deadliest drug problem. FDA estimates that more than 33 million Americans misused extended-release or long-acting opioids in 2007-up from 29 million 5 years earlier. The Centers for Disease Control and Prevention (CDC) documents a rise in deaths and emergency room visits related to prescription drug use, and unintentional overdose deaths involving opioids nearly quadrupled from about 3000 in 1999 to more than 11,000 in 2007.
Drug treatment programs are seeing more young patients coming in either addicted to opioid prescription drugs or in the first years of heroin use that started with opioids, explains Deni Carise, PhD, chief clinical officer at Phoenix House, a leading national drug abuse treatment provider. "People think that taking a prescription drug is okay, and the habits quickly get very expensive," she pointed out.
FDA's opioid REMS requires manufacturers to develop educational materials to make physicians and consumers more aware of the dangers of opioids, as well as their appropriate use in treating pain. It was announced in April as a central component to a federal campaign to reduce prescription drug diversion and abuse by 15% in 5 years. Led by the White House Office of National Drug Control Policy, the program also calls for more extensive monitoring of drug use by CDC and for the Drug Enforcement Agency (DEA) to crack down harder on "pill mills" and clinics offering easy access to pain meds. Because many adolescents initially obtain these drugs from family medicine cabinets or from friends, more federal and state "take-back" events will promote proper disposal of unused or expired medications. And the plan supports state prescription drug monitoring programs with databases to track prescriptions for certain drugs and inform physicians and pharmacies of excessive patient drug use.
To better educate prescribers in the appropriate use of these medications and to alert patients to dangers of drug misuse, FDA wants generic and brand opioid manufacturers to collectively design training materials for use by certified medical educational (CME) programs, which agency officials will scrutinize to ensure objectivity, accuracy and absence of promotional bias. The industry group also will develop common elements for Medication Guides that pharmacists will give patients.
An FDA advisory committee rejected such a voluntary educational campaign last July as too weak to curb abuse, and drug abuse groups want to expand the scope of the REMS to include immediate-release pain medications. This would include short-acting Vicodin (hydrocodone), which is the most widely prescribed drug in the United States, with 131 million prescriptions in 2010, according to IMS Health. The current program is limited to extended-release opioids, such as hydromorphone, morphine, oxycodone, oxymorphone, and tapentadol, because these contain a stronger dose of active ingredient and thus are more dangerous when abused.
The agency opted for this moderate approach as a first step in trying to tackle the problem because FDA lacks authority to limit physician prescribing, explained Janet Woodcock, director of the Center for Drug Evaluation and Research (CDER). Moreover, a limited distribution system for opioids with mandated physician and patient registration would create an oversight responsibility far beyond FDA's capabilities and generate fierce opposition from the medical community.
Instead, the Obama administration is asking Congress to enact legislation that mandates training on opioid use for physicians to obtain the DEA registration number needed to prescribe opiates and other controlled substances. But for now, the educational component of the national plan is optional for the 600,000 doctors and other health professionals licensed by DEA to prescribe controlled substances.
SEEKING NEW FORMULATIONS
The ultimate solution to the opioid drug problem is for manufacturers to formulate pain killers more resistant to abuse. The White House plan calls on FDA and the National Institute on Drug Abuse (NIDA) to collaborate on research for developing abuse-deterrent formulations of opioids, as well as pain therapies less attractive to non-medical users.
Yet, formulating such products is very challenging. King Pharmaceuticals (now part of Pfizer) had to recall painkiller Embeda (morphine/naltrexone) several times after it was approved in 2009 due to stability and dissolution problems related to its anti-abuse formulation; now it's unlikely to return to the market. Purdue Pharma's extended-release Palladone (hydromorphone) was associated with serious adverse events and pulled in 2005.
California-based Pain Therapeutics is developing Remoxy as a substitute for oxycodone. To demonstrate that its unattractive taste and texture will discourage abuse, the company designed a clinical study to document lower "drug liking" by potential abusers, which it hopes will pass muster with FDA.