Prescription drugs that are on the market have all attained stringent approval by the Food and Drug Administration (FDA), but not all of the drugs are prescribed in manners that adhere to FDA authorization.
Off-label prescribing — the act of prescribing a drug for uses, or in dosages, other than the ones stated on its label — is a rampant phenomenon that relies on physicians’ judgment, patients’ will and pharmaceutical companies’ information.
In the realm of oncology drugs, off-label prescribing is even more common than in the world of prescription drugs as a whole. Between 50 percent and 75 percent of oncology drugs are being administered off-label, according to the National Comprehensive Cancer Network, whose guidelines and statements are considered to be standard consensus in oncology.
Imbruvica — an oral treatment first approved in November 2013 for mantle-cell lymphoma (MCL), which is a rare and aggressive type of immune system cancer that hits 3,900 people in the U.S. per year — was once in the mix, but is now expected to be moving away from off-label use, in light of its second FDA approval for treatment of chronic lymphocytic leukemia (CLL), a more common type of blood cancer that hits 15,720 people in the U.S. per year.
Between its first FDA approval and this second approval on Feb. 12 of this year, an estimated 35 percent of Imbruvica’s sales were for off-label usage in CLL treatment — and this was while the drug was in the early stages of clinical trials for CLL — according to Deutsche Bank analyst Robyn Karnauskas. Back in January, Karnauskas had anticipated Imbruvica’s off-label sales to increase beyond 35 percent, on the heels of positive results from a late-stage CLL clinical trial.
For Imbruvica, off-label usage for CLL stemmed from initial belief that the first approval would have been for CLL, not the more rare MCL, and was further boosted by favorable CLL clinical trial results.
This is not always the case behind off-label oncology prescriptions. The driver often is practicality. Some cancers are especially rare, making it difficult for pharmaceutical companies to obtain enough subjects to perform the clinical trials necessary to gain FDA approval.
Desperate patients are acutely aware that a potential treatment may never gain FDA approval, and in oncology, early access to a treatment can be life saving. Patients often are willing to test new regimens that may benefit them, the drugs are there — albeit for a different patient demographic, type of illness or dosage — and physicians are legally able to prescribe as they see fit. This creates an environment especially conducive to off-label usage.
“While there is good scientific rational and clinical evidence for efficacy and safety in many indications beyond the label, use will be dependent upon the conversation between the physician and patient,” said Gregory Wade, an analyst with Wedbush Securities’ San Francisco office. “Physicians who prescribe drugs off-label possess the training and knowledge to do so safely.”
Even so, the practice undermines FDA standards, which stress rigorous studies and evidence to ensure safety and efficacy for each specific situation. By bypassing a complete FDA review, there always remains the possibility of inefficacy or harm from off-label use, experts say.
Off-label usage also poses potential benefits for pharmaceutical companies. Whether or not their drug is being clinically tested for the use for which it is being prescribed off-label, they benefit from the additional sales generated by a wider range of patients. Pharmaceutical companies whose drugs are not in clinical trials for additional uses stand to benefit even more. They can bypass the time and monetary costs of running clinical trials for off-label usage.
Given the potential incentives held by off-label usage for pharmaceutical companies, there is a caveat to the practice. Off-label prescribing — the physician side of the practice — is legal, but off-label promotion by pharmaceutical companies is illegal.
Pharmaceutical companies must maneuver a fine line between providing physicians with information about all possible treatments of a drug and promoting the drug for such off-label usage.
“Off-label marketing isn’t the norm and evidence suggests that companies spend a great deal of effort in compliance,” analyst Wade said.
Those that do engage in off-label marketing, though in the minority, face heavy fines. In September 2008, and January and September 2009, pharmaceutical companies Cephalon, Inc., Eli Lilly & Co. and Pfizer, Inc. each paid steep fines for off-label promotion, to the tune of $425 million, $1.4 billion and $2.3 billion, respectively.
Pharmacyclics’ senior director of public relations and corporate communications, Manisha Pai, said in an interview: “We don’t promote or track off-label use.”
Even without the role of off-label promotion, an estimated 20 percent of prescription drug sales are off-label, according to liability firm, Gilbert, LLP.
In the Feb. 12 conference call announcing Imbruvica’s second FDA approval, executive vice president of Pharmacyclics’ sales and marketing, Paula Boultbee, addressed the matter of off-label Imbruvica use in CLL patients, stating, “We don’t know very much about the patients that have been treated in spontaneous fashion by physicians without the label … but we do expect that with Imbruvica approved in the CLL space, it (off-label use) will change quite dramatically.”
Imbruvica’s approval for CLL treatment eliminates room for off-label prescribing in that specific population; but that does not mean that Imbruvica might not be prescribed off-label for another demographic, such as elderly patients who have not undergone chemotherapy, or for another type of cancer, such as Waldenstrom’s — a rare type of blood cancer that affects 1,500 people in the U.S. annually.
“As we don’t track off-label use, I can’t really speculate about whether Imbruvica’s off-label use in relation to CLL treatment has diminished, but I can say that Imbruvica is being tested in many clinical trials for other uses at this time,” Pai said.
Editor’s note: This article has been updated from an earlier version to clarify a quotation.
Homepage image screenshot via imbruvica.com