Safety and Security

The measure of success at FDA is not the number of facilities inspected or new drugs approved, or the speed of approval processes, says commissioner Margaret Hamburg. What's more important is to promote health, prevent illness, and prolong life by ensuring public access to safe, nutritious foods and innovative, safe, effective medical products—that according to an editorial by Hamburg and principal deputy commissioner Joshua Sharfstein in the June 11 issue of The New England Journal of Medicine. To fulfill its public health mission, FDA needs to help develop needed vaccines, prevent safety problems, and pursue opportunities to advance science.

Jill Wechsler

Those are encouraging words for pharmaceutical companies that have been hammered for pushing unsafe products on the market and hiding unfavorable safety information. Just as heartening is the call for more collaboration with the Centers for Medicare and Medicaid Services to "shorten the time from approval to reimbursement," particularly in the emerging area of personalized medicine.

Hamburg and Sharfstein acknowledge that there are tradeoffs between permitting access to new therapies and protecting consumers from hazardous products. A public health approach, they say, recognizes that the "potential good of a new medical product or policy must be balanced against the potential harm." The key factors include severity of illness, availability of alternative treatments, and the state of knowledge about individual responses. But FDA officials must often make difficult decisions without complete information.

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Weighing risks

Such risk calculations may lead to additional safety warnings on marketed drugs and restrictions on the use of new medications while sponsors and regulators gather data on long term safety and efficacy. The FDA Amendments Act of 2007 (FDAAA) gives FDA several new tools for ensuring drug safety through the product life cycle, such as Risk Evaluation and Mitigation Strategies (REMS) governing postmarket prescribing and surveillance. FDAAA also expands the agency's authority to require post-approval label changes when new safety issues arise, and to crack down on manufacturers that fail to conduct agreed-upon postmarketing studies. The law also mandates more extensive listing of clinical trials and study results on the ClinicalTrials.gov public Web site to ensure that safety issues arising during clinical research are fully disclosed to regulatory authorities and to the public.

How well these new authorities make drug use safer will be tested in a number of high-profile initiatives. The agency is currently weighing the risks and benefits of antipsychotics for children and adolescents. FDA advisors recently explored the viability of significant curbs on acetaminophen formulations and packaging to reduce incidences of liver toxicity with high doses. A REMS for erythropoiesis-stimulating agents (ESAs) is in the works, and possibly one for anti-wrinkle botulinum toxin products. Weight-loss treatments and the smoking cessation drug Chantix are on the agency's drug safety priority list. And there could be added risk management strategies for COX-2 inhibitors, antidepressants, and anti-epileptics.

The risk-control features of the REMS program face an important test in a new initiative to establish a broad REMS for the entire class of extended relief opioid medicines. This includes 24 brand-name and generic products, such as fentanyl patches, and oral drugs formulated with oxycodone, hydromorphone, methadone, morphine, and oxymorphone.

The aim is to ensure continued access to these medications, which are essential for patients suffering from chronic pain, while also curbing inappropriate prescribing, unintentional overdosing, and intentional abuse. Some 23 million prescriptions of these painkillers are dispensed annually to about 4 million patients in the US, even though long-acting opioids can cause respiratory distress when prescribed to the wrong patients or in too-high doses. These drugs also are open to abuse because they can be crushed or dissolved to permit a large dose to be taken at once; 12 million Americans over age 12 took pain relievers for nonmedical uses in 2007.

Setting Strategies

Instead of pulling these products off the market, FDA officials hope to improve prescribing through coordinated risk management. Under FDAAA, a REMS may consist of just a Medication Guide and a timetable for evaluation following approval. The next step is to devise a communication plan for conveying safety information to prescribers, pharmacists, and patients. The most high-risk drugs also have to establish Elements to Assure Safe Use, which can include special training or certification of health professionals; limited distribution to ensure that a drug is dispensed only to patients who meet certain criteria; patient surveillance to identify adverse reactions; and enrollment of patients in registries for long term oversight. Over the past 18 months, FDA has approved REMS for some 50 products, including drugs and medical products already on the market as well as new treatments.

FDA held an open meeting in May to discuss REMS strategies for opioids. More than 70 speakers presented opinions to a panel headed by Douglas Throckmorton, deputy director for the Center for Drug Evaluation and Research (CDER), and John Jenkins, director of CDER's Office of New Drugs. Parents of teens who died from OxyContin overdoses demanded that FDA remove such dangerous drugs from the market, while representatives of the pain community stressed the need for full access to these medicines, and warned that restricted distribution systems and complex oversight programs could be harmful to patients and costly to the healthcare system.

The opioid class REMS is unique in that it requires brand and generics manufacturers to jointly devise a single, shared system to monitor the safety and risks of dozens of products—a tricky task for fierce competitors. Pharmacists and providers want uniform education and certification programs that fit current work flows and the existing DEA (Drug Enforcement Agency) registration system. Manufacturers don't want to run the whole program, and are seeking strong participation by prescribers and dispensers, as well as the DEA, state licensing boards, and other parties. But FDA can only regulate pharma companies, not physicians.

While FDA digests these proposals and develops an REMS proposal for advisory committee consideration later this year, agency officials say they won't hold up the review and approval of new opioid products in the pipeline. Purdue Pharma is seeking FDA approval of a new oxycodone product, but has run into trouble documenting whether the drug really will deter abuse. King Pharmaceuticals has filed applications for two new formulations with anti-abuse claims.

Establishing a final REMS plan could take more than a year, and FDA may propose some interim industry actions during this process, such as added label warnings. Once FDA issues a REMS proposal for these drugs, it will be up to each manufacturer to file an implementation plan and carry it out, or face new penalties in the regulator's compliance toolbox.

Jill Wechsler is Pharmaceutical Executive's Washington correspondent. She can be reached at jwechsler@advanstar.com