FDA Pursues Delicate Balancing Act - Pharmaceutical Executive

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FDA Pursues Delicate Balancing Act


Pharmaceutical Executive


Jill Wechsler
A number of high-profile regulatory issues challenge the Food and Drug Administration's ability to balance potential harm and benefits to patients—both from gaining access to new treatments and by addressing safety threats from misused or adulterated products. The public outcry over shortages of critical cancer therapies and intravenous solutions, for example, raises questions about whether FDA endangers consumers more by permitting violative products on the market—or by shutting down facilities needed to produce important therapies. FDA officials say they take every step to avoid a plant closure and work hard to identify alternate quality sources, but can't permit marketing of contaminated products—especially injectible therapies.

FDA faces similar calculations about the potential for aggravating drug shortages when it moves to shutter drug compounding operations that fail to meet standards. Congress recently enacted legislation that bolsters FDA's authority to crack down on violative compounders, while permitting legitimate operators to continue providing services to hospitals and patients. However, it's not clear that the new voluntary registration program will do much to curb the bad actors, unless purchasers steer their business to quality compounders.

Efforts to curb counterfeit and substandard drug distribution similarly require a tricky FDA juggling act to permit access to less costly medicines while blocking distribution of fraudulent products. Many Americans appear eager to order drugs from unknown sources that offer lower prices. Maine has even passed a law authorizing import of cheaper drugs from "Canadian websites," despite warnings that this could bring in ineffective and unsafe medicines. Consumers believe that unregistered online operators provide perfectly sound medicines, and that FDA controls merely reflect pressures from pharma companies to reduce low-cost competition.

Balancing pain meds

Perhaps its most prominent safety vs. access issue involves regulation of dangerous opioid use while ensuring patient access to needed pain treatment. FDA recently agreed to tighter controls by the Drug Enforcement Agency (DEA) for widely used combination opioid treatments such as Vicodin. These drugs have benefitted for years by being listed on DEA Schedule III, where drugs are easier for doctors to prescribe, for patients to obtain, and for pharmacists to store and dispense. FDA has long opposed DEA "upscheduling" based on evidence that combination products are not as dangerous as full-strength opioids. But more deaths from opioid abuse prompted the agency to announce in October that it now supports the scheduling change.

At the same time, to ensure patient access to effective pain therapy, FDA made the surprise decision to approve a new, high-strength long-acting opioid, Zohydro, despite safety concerns and a high risk for abuse. This decision seems to counter agency support for developing products with anti-abuse capabilities, as outlined in guidance issued in January (2013). FDA delivered on that promise in April by authorizing Purdue Pharma to promote the abuse-deterrent features of its reformulated OxyContin. FDA further decided that it would not approve any generic versions of the original OxyContin formulation, which Purdue had stopped marketing.

The complexities of the regulatory status of these pain medicines, though, is seen in a contrary decision a month later, when FDA decided not to grant that same kind of protection from generic competition for Endo's reformulated Opana ER. Here, FDA concluded that despite formulation changes, the drug remained vulnerable to abuse by injection and snorting.

To manage risks, the new opioid Zohydro has to carry new labeling that FDA unveiled in September (2013) for all long-acting opioid drugs. Revised labels will advise doctors to prescribe treatment only to patients suffering very serious—not moderate—pain. The policy change was announced with great fanfare, but boxed warnings and added risk information seem unlikely to dissuade addicts from breaking the law.

Faster approvals


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The development and approval of more targeted personalized medicine is another high priority for FDA and pharma companies, and one that clearly involves weighing the benefits of fast approval against the risks of harm from undetected safety issues. A main strategy for achieving balance is to target testing and prescribing to those individuals more likely to benefit from a new drug or less likely to suffer adverse effects. For such therapies, FDA encourages sponsors to conduct smaller, faster and more targeted clinical studies to demonstrate effectiveness in a specific patient population.

At a briefing in October to unveil a new FDA report on "Paving the Way for Personalized Medicine," commissioner Margaret Hamburg described how a deeper understanding of the underlying mechanisms of disease has made it possible for FDA to approve more than 100 new drugs with specific labeling information on genetic biomarkers, such as a new treatment for cystic fibrosis effective in patients with a unique gene mutation. Agency scientists are further devising methods for refining dosing regimens by examining genetic factors that affect how much of a drug enters the blood stream for certain patient groups. FDA officials consequently look to approve targeted therapies based on less extensive safety data, in exchange for commitments to continue safety analysis in the postmarketing setting.

These approaches have been adopted most notably for cancer treatments, where very sick patients are willing to accept more risk. At the briefing, Richard Pazdur, director of the Office of Oncology & Hematology Products in FDA's Center for Drug Evaluation and Research, described how smaller clinical trials for targeted cancer therapies will be possible by using master protocols for all patients with certain biomarkers for diseases, and platforms for universal testing of biomarkers and diagnostics able to identify appropriate patient cohorts.

Yet some experts continue to complain that such approaches will let unsafe drugs on the market, and that more stringent policies are needed to limit how fast a new drug can be approved for even limited treatment. Some prominent clinicians have claimed that expedited reviews yield too many products with unanswered safety questions.

Pazdur responds that people now understand that as a new drug is used, new safety findings will emerge. If FDA is taking appropriate risks for accelerating approvals, some drugs eventually will come off the market, he acknowledged. And if that doesn't happen, he said, "we probably aren't taking appropriate risks."








Jill Wechsler is Pharm Exec's Washington correspondent. She can be reached at

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