A deeper look at doxepin and the FDA

Doxepin is an old drug that functions as a sedative and, at high doses, as an antidepressant. It goes by many names, including Silenor and Sinequan. On GoodRx, you can buy 30 doses of Sinequan for about $10, but Silenor costs at least $100. But these are two names for exactly the same chemical. Physicians have been able to write off-label prescriptions for doxepin since the drug was first approved in 1969. It’s a second-rate and unpopular drug relative to other antidepressants and sedatives, but the very expensive Silenor is still generating revenue for its parent company.

Scott Alexander interprets Silenor as an example of the FDA’s role in perpetuating the high costs of our healthcare system. The company that brought it to market, Somaxon, spent $170 million on 3-4 phase III trials and other costs of winning FDA approval for its brand name of doxepin as an insomnia drug. Why don’t physicians just prescribe the much cheaper Sinequan?

...there are various regulations that make off label prescriptions less convenient than the usual type, so most people stick with Silenor...

So the idea is that FDA approval creates trivial inconveniences for physicians writing off-label prescriptions. This creates an opportunity for drug companies to needlessly spend the money to get FDA approval for their brand so that physicians can prescribe it on-label. This alleviates a trivial inconvenience created by the FDA, but at tremendous cost to the public.

We should interrogate this hypothesis. Is it really inconvenient enough to write off-label prescriptions that it creates a market for companies to profit?

I spoke with a psychiatrist who’s been practicing for decades, who had this to say about writing off-label prescriptions:

Once a drug has been approved by the FDA for any indication, a physician can prescribe it for anything without hassle or limitation. On occasion – but certainly not in a case like Silenor – there may be insurance hassles, refusal to cover medication for which the indication is suspect.

So the idea that off-label prescription writing is inconvenient enough to make physicians prefer expensive Silenor over cheap generic doxepin is controversial. But none of these claims are precise. We could be dealing with any number of physician concerns. It might take more time to prescribe off-label, patients may request a particular brand name, there might be concerns about the evidence basis of off-label prescriptions, it takes time to learn about the relative costs of Silenor vs. generic doxepin, and evaluating evidence takes time relative to just prescribing whatever is FDA approved for a given indication.

In any case, what you might miss if you assume that predatory practices = profit is that Silenor has been a disaster for its manufacturer. It cost Somaxon $170 million to get Silenor FDA approved for insomnia. They’re making a couple million dollars per quarter in revenue (not profit).

If you’re a critic of the FDA, you might look at that $170 million price tag and think, “it’s crazy that the FDA imposes such high costs to bring a drug to market, and that it creates the opportunity for companies to profit off of needless regulations.” But you could also look at that $170 million as a punishment for corporate parasitism. Pernix Therapeutics acquired Somaxon, and through it, its FDA-approved Silenor, for $25 million in 2012 - $145 million less than Somaxon paid to get it approved just a couple years before! Pernix itself went bankrupt in 2019.

It’s not at all clear that the story of Silenor is best interpreted as an indictment of the FDA. Instead, the FDA comes out looking to me like it successfully imposed a devastating cost on a company trying to use marketing and regulatory manipulations to parasitize the healthcare system. That doesn’t mean the FDA doesn’t have major problems. I’d be hesitant to assume that other stories about the nature of FDA regulation making drugs unnecessarily expensive or unavailable are false, just because this one is more complex than it first appears.

What I would take away from this is the complexities of the healthcare system are going to make the process of evaluating the systemic causes of “weird healthcare outcomes” equally complex. Such an investigation requires considering the history of both the active ingredient of the drug and the particular brand in question; the working conditions and pressures that doctors face; the business practices of companies and regulatory practices of the FDA; and the financial outcomes both for the healthcare system and the company marketing the drug.

My guess is that a lot of even doctors’ attitudes about the healthcare system are shaped by strong gut reactions to vivid stories and personal experiences of absurd and frustrating problems with the healthcare system. They share those stories, which get simplified and enhanced for transmissibility like any other meme. The details are lost. It’s a gigantic game of telephone.

The system might still be absurd and dysfunctional. But the precise nature of that absurdity and dysfunction might be quite different from what best suits the transmissibility of a healthcare story. And understanding those mechanistic details is important for understanding what actually needs to be done to make the situation any better. Furthermore, if those stories comprise most of the “data” that forms the judgments of activists interested in changing the healthcare system, there’s a huge risk of bias.

One way of cutting through to clearer insight might be to focus on proposing particular changes to the system, then making predictions about what effects this might have. Being generally critical of the FDA is a fine stance to have, but it’s not very enlightening about what in particular needs to be done to improve things. In the case of Silenor, it seems like the outcome is actually pretty good: a predatory company blew its own foot off trying to profit off a pointless drug because the FDA required it to pay for trials demonstrating the efficacy of a drug already widely known to be effective, just to achieve “on-label” status.

I’m highly sympathetic to the idea that there should be a better way to promote FDA approved drugs known to be effective for some off-label use to a similar status as those that have passed a phase III trial. Whatever it is, it’s going to have to balance the needs of patients, physicians, regulators, pharma companies, and, perhaps insurers. It will also have to balance a range of policy goals including how we incentivize and evaluate innovation, protect and police physicians, and manage healthcare costs and access. And then there’s the little problem of getting that dream solution implemented.

For most people, myself very much included, it seems best to focus on gathering data about why the system currently produces the outcomes it does, and pursuing a deeper understanding of those Healthcare System Disaster Stories circulating around.