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Off-label, But Lucrative
from February/March 2023
Big pharma profits when doctors prescribe a drug for a disorder other than the one that earned FDA approval. The practice ranges from evidence-based to highly egregious.
BY NAVPREET DHILLON
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One in five prescriptions written in the United States is for a drug that hasn’t been approved for what’s ailing the patient.
That factoid from the Agency for Healthcare Research and Quality website casts a shadow of doubt over many of the prescriptions known as “off-label.”
It’s when doctors prescribe a drug for a disorder other than the one that earned Food and Drug Administration (FDA) approval. They might, for example, order a diabetes drug for a patient who’s not diabetic but wants to lose weight.
Off-label prescribing is often appropriate, and it’s become an everyday occurrence. The most common off-label prescriptions are cardiac medications, anticonvulsants and antiasthmatics. They’re most often used to treat depression, bipolar disorder and insomnia.
But up to 73% of off-label prescriptions aren’t backed by scientific research that would establish whether they’re effective for uses other than those the FDA certified, says Dr. Randall Stafford, a Stanford School of Medicine professor and director of the university’s Program on Prevention Outcomes and Practices.
Instead, medical providers prescribe drugs off-label because of anecdotal evidence, under-the-counter marketing and lax FDA supervision, Stafford notes.
They don’t always work, according to Dr. Caleb Alexander, a pharmacoepidemiologist and co-founding director of Johns Hopkins’ Center for Drug Safety and Effectiveness.
“Off-label use runs the gamut from highly evidence-based to grossly egregious use—and everything in between,” Alexander says. “But the concern is that many off-label uses are not well supported by clinical evidence.”
PROBLEMS AT THE FDA
Stafford conducted a study revealing the limitations of the FDA. Take gabapentin (Neurontin), for example, an anticonvulsant off-label prescribed for bipolar disorder and nerve pain.
As many as 83% of gabapentin prescriptions were off-label, the highest percentage of any drug Stafford studied. What’s more, 80% of those off-label prescriptions were not backed by scientific support.
Gabapentin’s manufacturer, the Warner-Lambert division of Pfizer (PFE), paid more than $430 million in damages in 2004 for marketing the drug for bipolar disorder and nerve pain even when supplemental studies found a placebo performed better.
The settlement amounted to a slap on the wrist for Pfizer compared to the billions of dollars gabapentin made the company, as Jeanne Lenzer wrote in a study published in the National Library of Medicine. Plus, gabapentin is still prescribed off-label for severe cases of bipolar disorder, depression and nerve pain.
“Old habits die hard,” Alexander observes. “Some of these prescribing patterns are heavily entrenched and have been learned and taught among a generation or two of providers and patients.”
While medical practitioners attempt to make the best decisions for patients, clinical trials should form the backbone of prescriptions, Stafford says.
Yet legislation mandates that the FDA keep its hands off of active clinical practice decisions, allowing providers to base prescriptions on their own knowledge.
“While it might look at post-market use—about how drugs are being used,” Stafford says of the FDA, “it doesn’t have the ability to say, ‘Well, that’s wrong, you should stop doing that.’”
WINNING OVER THE FDA
When manufacturers do find compelling evidence for additional uses for a medication, they can submit a supplemental new drug application (sNDA) to the FDA. An sNDA provides clinical studies for new uses and enables the manufacturer to market the drug for additional approval.
In a prime example of an sNDA, the FDA in 1990 approved the drug lamotrigine (Lamictal) to combat epileptic seizures. Then it approved the drug with an sNDA again in 2003 to treat bipolar disorder.
The blockbuster drug semaglutide, known as Ozempic and Wegovy, won FDA approval as a Type 2 diabetes management drug and retained an sNDA approval for reducing cardiovascular risk from Type 2 diabetes and weight management.
This drug, manufactured by Novo Nordisk (NVO), gained traction for its ability to help users drop around 15% of their weight, a number that caught social media’s attention.
It’s no secret that weight loss tips dominate social media conversations—but Ozempic and Wegovy took that to a new level. The Wegovy website labels it as a weight loss drug for obesity while the Ozempic website specifies it’s for lowering blood sugar and isn’t meant for weight loss.
The same compound but in different doses, semaglutide, quickly took off as celebrities credited their weight loss to both Wegovy and Ozempic, resulting in a shortage that has left Type 2 diabetes patients without the necessary drug.
Dr. Disha Narang, a diabetes expert and endocrinologist at Northwestern Medical Group in Lake Forest, Illinois, maintains that while off-label prescribing for semaglutide led to its approval for weight loss, the shortage reveals healthcare providers have misinterpreted the indication.
“Obesity and weight management is chronic,” Narang says. “These drugs are meant to be used longer-term for this disease, so they’re not for short term use nor have they been indicated as such. But because of the social media surrounding it, people, unfortunately, are using it for that purpose.”
It remains unclear how patients react to semaglutide if taken short-term. Discontinued use likely leads to a weight rebound, but the long-term effects remain unknown for people without blood sugar problems, obesity or diabetes who have taken semaglutide for a period of months.
WHO’S TO BLAME
Because of a lack of funding, the FDA tends not to monitor drug use post-market. That means it can’t follow up on long-term effects of an approved drug.
Semaglutide, for example, underwent a two-year study, but for a disease that requires lifelong management, researchers like Stafford raise concerns about the consequences over time.
“It’s not completely clear that the FDA looked closely enough at long-term potential adverse effects of using this injectable drug,” Stafford says. “But it is certainly all the rage.”
Even in the development process, manufacturers compare the drug against a placebo, not against competing drugs. The lack of comparison prevents both the FDA and consumers from understanding whether the drug is an innovation and adds value to the system as a whole, or if it’s another drug released to saturate the market and liable to cause greater risk for unstudied off-label use.
Then, too, the FDA relies on funding from pharmaceutical manufacturers and thus isn’t entirely independent, observers say. As the dictator of what enters the market, the FDA needs better federal funding to serve the public and its needs, they conclude.
“Do we want an FDA that is dependent on corporate fees for its work?” Stafford asks. “Or do we want an FDA that is more oriented towards a societal or a public health viewpoint?”
