Safety Concerns and Shortages Challenge Pharma

The proper production of safe and effective prescription drugs is central to a number of important regulatory and public policy 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 anxious to resolve shortages of important therapies and ensure access to needed medicines. FDA is a prominent player in the crackdown on opioid abuse and oversight of drug imports, and is also keeping an eye on possible disruptions in supplies for patients. These developments add to pressure on manufacturers to secure supply chains, comply with GMPs, and to develop products that resist tampering and abuse.

Jill Wechsler

Shortages limit access

From high-security prisons to cancer clinics, crucial drug shortages are placing attention on drug manufacturing and 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 difficulties that have led to plant closures. Generic-drug manufacturer Teva, for example, had to shut down a California injectable drug facility after an FDA inspection cited numerous GMP violations. Compounding the difficulties is the increased import of active ingredients from foreign suppliers, China in particular.

A March 2011 survey by the Premiere Healthcare Alliance found that last year, more than 240 drugs were either in short supply or unavailable in the US. Efforts to obtain alternative therapies boosted hospital and provider costs by at least $200 million. Even worse, shifts to different medicines appear to boost medication errors as practitioners make mistakes mixing and administering less familiar products.

In response, FDA has moved to 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 using their products for capital punishment.

The situation has prompted calls to bolster FDA 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.

Managing imports

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 an automated Predictive Risk-Based Evaluation for Dynamic Import Compliance Targeting computer system, known as PREDICT, to replace its outdated import screening process, which cannot handle the approximately 24 million shipments expected to arrive 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 an approach that reaches "back further to where products are manufactured" to ensure that drugs meet quality standards beginning where they are produced, explained FDA Commissioner Margaret Hamburg at an April 2011 hearing before the House Energy and Commerce Committee. FDA critics complained, however, 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.

The agency would gain more tools for managing imports, moreover, from proposed drug-safety legislation that authorizes FDA 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. The bill, sponsored by Rep. John Dingell (D-MI), 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 the collection of more manufacturing information.

Crack down on opioids

In the US, the most alarming drug-safety issue involves overuse, misuse, and abuse of extended-release opioid drugs. FDA and manufacturers have been struggling to devise a Risk Evaluation and Mitigation Strategy (REMS) since 2009 to promote safe use of these medications. The task is complicated, however, by the use of these powerful painkillers by millions of individuals suffering acute pain, which generates opposition from patient advocates and physicians to any policies likely to limit access to these important therapies.

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 five 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, chief clinical officer at Phoenix House, the 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 unveiled its opioid REMS in April 2011 as a central component to a federal campaign to reduce prescription-drug diversion and abuse by 15% in five years. The REMS requires manufacturers to develop educational materials that will make physicians and consumers more aware of the dangers of opioids, as well as their appropriate use in treating pain. The broader program, which is led by White House Office of National Drug Control director Gil Kerlikowske, also calls for more extensive monitoring of drug use by the CDC, and for the Drug Enforcement Agency (DEA) to crack down on "pill mills" and clinics offering easy access to pain medication. 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. Also, 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 continuing medical educational (CME) programs, which agency officials will scrutinize to ensure objectivity, accuracy, and absence of promotional bias (see sidebar, "Pharma's influence on CME"). The industry group also will develop common elements for Medication Guides that pharmacists will give patients.

Pharma‘s influence on continuing medical education (CME)

Elements to Assure Safe Use (ETASU) in the REMS will involve a collective strategy for evaluating the effectiveness of educational and monitoring efforts in six months, 12 months, and annually thereafter. The assessment will report on how many prescribers complete educational programs and if the REMS has any impact on patient access to opioids—for both appropriate and inappropriate uses. FDA has required similar REMS for two recently approved pain-relief products (Covidien's Exalgo and Purdue Pharma's OxyContin), and these would be incorporated into the new class-wide REMS.

Limited authority

Although FDA advisory committees rejected such a voluntary educational campaign last July as too weak to curb abuse, the agency is adopting this moderate approach as a first step in trying to tackle the problem. Janet Woodcock, director of the Center for Drug Evaluation and Research (CDER), noted that FDA can require drug manufacturers to develop educational materials, but lacks the authority to control physician prescribing. 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 opioids 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. In 2000, Congress approved the Drug Addiction Treatment Act, which requires 8 hours of special training for physicians to prescribe and dispense buprenorphine (Subutex and Suboxone) for treating opioid addiction, but this involves much more limited drug use and far fewer physicians. The prospect of additional Congressional action in the near future is fairly dim because both the medical pain-management community and pharmaceutical industry oppose mandatory training or other initiatives that could limit access to pain medications.

At the same time, drug-abuse groups would like to expand the scope of the REMS to include immediate-release pain medications, such as short-acting Vicodin (hydrocodone), which is the most widely prescribed drug in the US (131 million prescriptions were written for Vicodin 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 drugs contain a stronger dose of active ingredient and, thus, are more dangerous when abused.

Just how some 16 brand and generic-drug firms will devise a singled shared system for educating prescribers and patients and for monitoring the program's impact is unclear. While components of the educational materials and Medication Guides will apply to all drugs in the class, each manufacturer also will have to provide drug-specific information. A common approach for assessing the effectiveness of the REMS will involve independent audits of training quality, evaluation of providers' understanding of opioid risks, and a broader surveillance plan to detect misuse, abuse, overdose, addiction, and death resulting from specific drugs.

CDER's Office of Surveillance and Epidemiology may play a role by tapping databases on prescribing, emergency room visits, and other indicators that could help evaluate the program's impact. In the end, all affected manufacturers may submit a similar REMS to FDA, with appendices on their specific drug. FDA wants to receive the industry REMS plan by fall 2011 so that the program can go into effect in early 2012.

The ultimate solution to the opioid misuse 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 and testing abuse-deterrent formulations, as well as pain therapies less attractive to nonmedical users. FDA also is charged with issuing guidance in two years on developing and testing such products and on ways to assess performance in the real world.

Clearer standards for studying tamper-resistance and for conducting clinical trials would be useful to manufacturers developing medicines with anti-abuse features, according to the Pharmaceutical Research and Manufacturers of America (PhRMA), which testified before an April 2011 Energy & Commerce subcommittee hearing on combating prescription drug abuse. PhRMA also noted the importance of obtaining adequate reimbursement and coverage for addiction treatments.

In fact, formulating abuse-resistant products can be 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; apparently it may not return to the market. Purdue Pharma's extended-release Palladone (hydromorphone) was associated with serious adverse events and pulled in 2005. Pain Therapeutics is developing abuse resistant 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.

Jill Wechsler is Pharmaceutical Technology's Washington editor, 7715 Rocton Ave., Chevy Chase, MD 20815, tel. 301.656.4634, jwechsler@advanstar.com.