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Off-label Use: The Fine Line Between Illegal Promotion and Useful Information

BioWorld Perspectives Contributing Writer

I can only imagine the frustration physicians must feel when patients come in armed with enough knowledge to make them overconfident in their own ability to practice medicine. Patient, heal thyself.

So when a neurologist prescribed a calcium-channel blocker indicated for angina and arrhythmia for my husband's frequent and crippling migraines, I tried very hard to keep the skepticism out of my voice as I benignly questioned her choice of pharmacotherapy.

Doctors can prescribe drugs off-label, or outside of the intended use according to their label as approved by the FDA. Drug makers, however, cannot advertise or promote use of their products off-label. The regulations are in place to protect patients from use of therapies in indications for which there is little or no evidence to support their use.

But consider the therapy that, according to solid evidence, works in areas for which it is not FDA-approved. My husband's prescribed calcium-channel blocker, for example, has shown to be effective in treating migraines, but is a generic and it is unlikely that a pharmaceutical company will ever allocate the necessary resources for a clinical trial simply to add a migraine indication to the label. A drug maker is in the business to sell drugs, and somehow must communicate information about a therapy without running afoul of the law. Where is the line between a drug maker informing physicians of this drug's potential benefit in an off-label indication and illegal promotion?

Companies That Have Paid Out for Off-Label Promotion
Federal authorities have taken drug makers to task increasingly over the years for alleged illegal promotion, typically through the False Claims Act. In 2010 alone, all of the top ten cases settled involved health care – for a total of $2.7 billion, out of the year's $3.16 billion overall – and eight of those involved pharmaceutical companies.

Companies have paid relatively paltry sums compared to their bottom lines – Novo Nordisk A/S recently agreed to pay $25 million to resolve charges of illegally promoting its hemostasis management drug, NovoSeven – but there have been settlements of more than $500 million just in the past two years alone.

These settlements will hardly be the last, as the government continues its work to eradicate illegal marketing activities. But are authorities just nit-picking? Do overly strict regulations hamper drug makers getting beneficial (but unapproved) therapies into the hands of patients?

A regulatory body is in place to protect patients from ineffective and unsafe drugs and physicians are responsible for providing patients with the best available treatment for their conditions. Where does the drug maker fit in to this scenario? A company, armed with data from clinical trials, can talk to regulators about label changes, but cannot talk to doctors or patients about these data until the label change is approved.

So who passes on the information? Enter the company's medical science liaison, who ensures that data is getting into the hands of doctors who ask for it (and can interpret it). Key opinion leaders play a role here too, as these independent experts sift through mountains of clinical data and discuss guidelines and practices with folks downstream in the community setting. Armed with a body of evidence and guidelines to back a prescribing decision, another player enters the fray – insurance companies. Doctors can prescribe as they see fit, but do insurance companies have to cover the costs?

Providing Coverage for Off-label Prescriptions
While off-label promotion is the purview of the Justice department, certain off-label prescribing is for all intents and purposes sanctioned by behemoth entities such as Medicare, and guided by national compendia. In 1993, a portion of the Omnibus Reconciliation Act legally required Medicare to cover an off-label use of a cancer drug if it is in the drug compendia, or is supported by peer-reviewed articles in certain journals outlined by Medicare.

In oncology, for example, the major compendium in oncology recognized by the Centers for Medicare and Medicaid Services is provided by the National Comprehensive Cancer Network (NCCN). The NCCN bridges a chasm between the regulatory function of the FDA and the practicalities of daily medical practice. Oncologists have long discussed use of oncologic agents off-label; NCCN estimates 50 percent to 75 percent of all uses of drugs and biologics in cancer care in the U.S. are off-label (and that figure jumps even higher in the pediatric cancer population). Many widespread anticancer drugs do not have an FDA-approved label for all the indications under which they can be effectively used, and often cancers are so rare that it is difficult to conduct a large enough clinical trial to obtain evidence necessary to support an approval. But consider the case of the child diagnosed with a rare pediatric cancer – if your physician believes a particular drug will treat or even trigger remission in your child and has evidence to back that up, are you going to say, sorry doc, but it's not on the label? Or imagine your elderly father is entering palliative care and wishes to take a drug that will extend his life for a few more months so he can see his grandchild graduate from high school. Would you support his choice if he wanted an off-label therapy? These scenarios presuppose a preponderance of evidence and well-informed physician, but even if that isn't the case, would you care how your doctor found out about the drug's off-label use in that indication? And perhaps more importantly, would you feel more or less certain of your physician's drug of choice if he learned about it by seeking information on his own versus industry promotion?

The line between a drug maker informing physicians of a drug's potential benefit in an off-label indication and illegal promotion just might be a fluid one, and where you draw it depends on your perspective – drug maker, patient, physician, regulator. In the future, whether regulations are strengthened, relaxed or rearranged into a new entity, the guiding light should be the reason the stakeholders are all playing the game – the patient.