Compounding the $750-A-Pill Mess

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When Turing Pharmaceuticals bought Impax Pharmaceuticals, the sole supplier of the antiparasitic drug Daraprim, and raised the price more than 50-fold, patients and doctors were furious. Then, of course, politicians got a piece of the action.

But, moral outrage is an easy narrative and so a lot has been left out of the story.

Daraprim is used to treat toxoplasmosis, a disease that results from infection by the common Toxoplasma gondii parasite (60 million Americans carry it, according to the Centers for Disease Control and Prevention). And though the disease is rare, it became "famous" during the time before effective AIDS drugs were available to restore the immune systems of those who were infected by HIV. It is rarely harmful in individuals with functioning immune systems.

Even with antiretroviral therapy taking AIDS mostly out of the equation, there are still up to 2,000 people in the United States with weakened immune systems who become ill from the infection, most often in the form of toxoplasmosis encephalitis. This group is primarily made up of cancer patients who are undergoing chemotherapy, those receiving immunosurpressant drugs following organ transplants, and, sometimes, pregnant women.

The drug went from just over $13 to $750, which was a lot for a 60-year-old product. The media storm was intense, politicians engaged in populist rhetoric about price gouging.

And then it got even stranger: Imprimis Pharmaceuticals, a San Diego-based pharmaceutical company that "is dedicated to delivering high quality and innovative medicines to physicians and patients at affordable prices," announced an alternative, which they intend to sell for one dollar. Imprimus uses compounding pharmacies to make drugs.

Compounding was once the standard pharmacies would make a formula for a patient. A desire for consistency and safety regulation made mass production the norm in the 20th century. Imprimis announced earlier this week that it will make and sell a pill that contains pyrimethamine the generic name of Daraprim and leucovorin, a second drug, which is co-prescribed along with it to offset bone marrow toxicity.

The best part, at least on the surface, is the cost it announced: The company has an agreement with Express Scripts to charge $1 per pill, far less than the $750 Turing list price, and even less than the $13.50 per pill that was being charged by Impax before they sold out to Turing, because they couldn't make the numbers work, even at $13.50 per pill. Turing says there are legal, regulatory, and safety arguments which make Imprimis' plan unworkable. Is there any merit to those arguments? The answer is less simple than news media stories make it out to be.

Turing correctly claims that there is no FDA-approved pill that is a combination of pyrimethamine and leucovorin. Leucovorin is prescribed together with pyrimethamine, but it is a different pill. Imprimis argues that this difference is trivial and irrelevant.

Any company can make Daraprim/pyrimethamine, the patent ran out decades ago, but Turing maintains that selling it as part of a two-drug combination would violate FDA regulations, and potentially be dangerous.

The arguments need to be discussed. First, the legal aspect: The FDA does allow exemptions for compounding pharmacies that permit them to become outsourcing facilities if certain conditions are met: "An outsourcing facility will be able to qualify for exemptions from the FDA approval requirements and the requirement to label products with adequate directions for use, but not the exemption from current good manufacturing practices (CGMP)."

What about safety? Putting two separate, safe, approved drugs already used together into one pill could theoretically be dangerous, but it is very unlikely. Any undesirable interaction between the two would have been noted long ago, since they have been co-administered. The chance of the two drugs reacting with each other inside the new pill is essentially zero. Solids rarely react with each other, even when mixed together. With regard to the quality of the Imprimus drug, pyrimethamine is extremely simple to synthesize, and any impurities that might be formed during the synthesis will be easily detectable and removed under CGMP. For that reason, the quality of the drug produced by either Turing or Imprimus should be high.

Yet the safety aspect is more nuanced than that. The levels of all drug in the blood are affected by a number of parameters, such as absorption, particle size and crystal form. This will not be measured as part of the normal FDA protocol, and so Turing has a legitimate point.

It would seem that Imprimus is being allowed a little FDA leeway here. There is more than science at stake, though, there is also the matter of the pocketbooks of patients and companies. If Daraprim could be made and sold for $1 a real viable business model someone would have done it long ago. If not, then it is a publicity stunt a marketing strategy, or perhaps even political. It will be interesting to see how this plays out.