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    Drug insights from a whistleblower


    Alan Cassels

    Are broken bones “hiding in plain sight” of heartburn meds?

     

    LAST YEAR MORE THAN 30,000 people in Greater Victoria took a pill from a class of drugs called Proton Pump Inhibitors (PPIs). This class includes drugs like omeprazole (Losec), esomeprazole (Nexium), rabeprazole (Pariet) or pantoprazole (Pantaloc). They are effective weapons in the fight against the scourge of modern heartburn, or what doctors call Gastro-esophageal Reflux Disease (GERD). Among the most popular and highest-selling of any drug class in the history of the world, PPIs have been an enormous success story both for the companies that make them, and the tens of millions of people around the world who swallow them every day.

    For many people, PPIs effectively suppress stomach acid in a way that makes the burning discomfort in your throat a long-forgotten memory. They work through blocking an enzyme in the wall of the stomach that produces acid. PPI is often a physician’s first choice of drug when a patient shows up complaining about heartburn.

    And did I say they were popular? In BC, nearly half a million people filled a PPI prescription last year, and in some parts of Canada, up to a third of the over-65 population may be chronically—that is, daily—swallowing a PPI.

    All of this comes with a hefty cost. At one point, British Columbians (through Pharmacare, extended health insurance and out-of-pocket payments) were spending $100 million every year on PPIs. That financial toll has dropped in recent years (down to about $60 million) due to PPIs coming off patent, allowing generic companies to sell cheaper versions of these drugs.

    Clearly, the massive consumption of even an effective drug raises many questions, the first being: Is there really an epidemic of heartburn in Canada? Is it wise to jump straight to a pill when there are several non-drug ways to prevent heartburn? If you really do need a drug, why this one? And lastly, if these drugs effectively relieve short-term heartburn, are they also safe if taken for months or years on end? Remember, stomach acid plays a key role in digestion.

    Because so many people take them, even if adverse effects are considered rare—occurring somewhere between one in 1,000 to one in 10,000 patients—the toll of injury could indeed be quite large. And many, many people will take them longer than the 4-8 weeks recommended for treating heartburn.

    The first PPI came on the market 30 years ago, and now there are six different ones available. I was drawn to research on the newest drug in this class, a product called dexlansoprazole (Dexilant), because of a question of rare but potential serious adverse effects. On PPIs in general, the medical literature contains no shortage of warning signals, which tells me that long-term chemical alteration of human stomach acid may be wreaking havoc on other body systems, raising rates of C. difficile infections, pneumonia and even possibly gastric cancers.

    There are numerous precautions listed in the Canadian dexlansoprazole product monograph, but I was drawn to the bottom of page four which read: “Several published observational studies suggest that PPI therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist, or spine. The risk of fracture was increased in patients who received high-dose, defined as multiple daily doses, and long-term PPI therapy (a year or longer). Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated.” (Italics added.)

    Because patent-protected drugs are the newest and most widely promoted, I suspect that dexlansoprazole (still sold under patent) is the kind of drug that doctors in BC are currently stocking in their sample cupboards.

     

    NOAH NATHAN worked for Takeda, a pharmaceutical company, when it launched dexlansoprazole in 2009, under the brand name Kapidex (which was changed to Dexilant a year later). He was among the first salespeople in America to promote it.

    Speaking to me from his home in Ellicott City, just outside of Baltimore, Maryland, he told me he loved his job as a pharma sales rep. To keep the sales reps happy, he said, “the company treated us really well and spared no expense.” He had a company car and an expense account. During his 15-year career at Takeda, he was often among the top 10 percent in sales, and won awards including an all-expenses-paid trip to Australia.

     

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    Whistleblower Noah Nathan

     

    His sales area was in Virginia, just outside of Washington, DC and his days would consist of driving around, making calls on doctors including gastroenterologists, ENTs (Ear, Nose Throat) specialists, and rheumatologists, pitching his company’s drugs, including Dexilant. In the course of his work, he fed a lot of physicians and their staff.

    “I really went for the comfort food,” he said, “rotisserie chicken, meatloaf with potatoes and gravy, that sort of thing.” He explained that the food might win him a valuable minute or two to talk up his products. Getting that face-time was crucial: “There’s such a big difference in prescribing, between those [doctors] who see us sales reps and those who don’t.”

    Yet over time, all of this delivery of food, samples, and information was starting to give Nathan indigestion. There was something about dexlansoprazole that didn’t exactly go down easy with him. He worried about the side effects and the dosages.

    When dexlansoprazole came to the market, Nathan explained, it came in two dose sizes—30mg and 60mg. The company tried to get a 90mg dose approved, but it was turned down. As a sales rep, however, it was only the higher 60mg tablet being promoted. All the sales materials were built around the 60mg dose. In fact, Noah explained, the newer company reps often didn’t even know about the 30mg dose, and many doctors in the field didn’t either. Currently in North America, more than 90 percent of the prescriptions for dexlansoprazole are in the higher 60mg doses.

    When dexlansoprazole was being reviewed by the US FDA to determine whether the drug should be allowed on the market, two FDA reviewers didn’t like the look of it. In their judgment, one of the reviewers wrote that not only was there no additional benefit of dexlansoprazole over the other five PPIs already on the US market, but that the evidence showed a higher incidence of fracture/injury-related adverse events with dexlansoprazole compared to other drugs.

    To grant the company marketing approval, the FDA required the company to carry out a “post-marketing clinical trial.” Basically, the FDA allowed dexlansoprazole on the market as long as Takeda promised to produce additional safety data, which was due to the FDA in December 2011. Over seven years later, no results have been posted to the FDA website.

    Nathan became an unexpected whistleblower and later an author. In his self-published book, Heartburn, Broken Bones, and the False Claims Act: Nathan v. Takeda Pharmaceuticals—Why You Should Care About the Case You Never Heard Of, he estimates that half a million Americans are taking 60mg doses of dexlansoprazole. The court case that he launched in 2009, and which ended in 2014, was premised on the issue that the company was likely promoting the drug “off label” for the higher dose, possibly putting patients at risk for fractures and other complications related to high dose PPIs. Promoting a drug for unapproved uses is illegal in the US, yet quite hard to prove, even if you’re someone like Noah Nathan with insider knowledge on how the company worked. After gathering further data (including wearing a wire to record company meetings) his case was rejected. His case probably wasn’t as solid as it needed to be to pass the court’s strict standards, but as he told me, had he been in a different state, things could have looked a lot differently. He said that “the courts ruled against me, while potentially putting American patients at risk.”

    Over those five years, Nathan lost his marriage, his job, and the case that could have strengthened safety precautions for other patients. Admittedly he was outgunned, facing off against some of the biggest law firms money could buy.

    I asked him if it was worth it, and he was quick to admit “being a whistleblower is hard,” but he’s more worried about the overall issues for public health. It’s possible that Nathan vs. Takeda might set a dangerous precedent, making it harder for other whistleblowers to succeed. Ultimately, he thinks that justice will eventually be done: “public opinion will eventually catch up,” he said, “when the lawsuits start piling up and people are suing for bone fractures related to the drug.” He adds, “for sure, there are broken bones out there, hiding in plain sight.”

    The lesson here is a precautionary one—that effective drugs in the short term can often wreak havoc in the long term. Taking any new drug is often a gamble, and the statement in the product monograph to “use the lowest dose for the shortest period of time” is an axiom that stands the test of time not only for PPIs, but for almost all drugs.

    Victoria resident Alan Cassels has spent 25 years researching and writing about pharmaceuticals. He currently works at UBC.

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