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Posted by on Feb 16, 2012 in Business, Health | 12 comments

Methotrexate: Yet Another Shortage Of A Lifesaving Drug Because Of Manufacturer Neglect

For me, the drug methotrexate is the difference between discomfort and comfort. For children with certain forms of leukemia, it is the difference between life and death. And yet another cautionary tale about regulation of the profit-greedy American drug industry.

Methotrexate has been around for six decades and has long proved to be effective against acute lymphoblastic leukemia (ALL), which strikes thousand children each year, as well as osteogenic sarcoma. In injectable preservative-free form, it is nothing less than a lifelong cure for many sufferers. I take a tablet form of methotrexate to manage my rheumatoid arthritis. It is inexpensive compared to the rheumatoid arthritis drugs that are television commercial staples and I am thankful that it works for me. For other suffers, it does not.

There is a shortage of preservation-free injectable methotrexate because yet another drugmaker has been cited for running filthy operations.

Ben Venue Laboratories of Bedford, Ohio, was shut down in November after flunking yet another FDA inspection.

“If you want to read something to give you nightmares, you can look at the FDA 483 inspection form,” says Erin Fox, an expert on drug shortages at the University of Utah. “You can read about mold on the walls and rust from machinery falling into the vials. It really provides a very grim picture of a crumbling factory.”

The same lab is responsible for another recent and far-reaching drug shortage involving Doxil, a drug relied on by thousands of patients with ovarian and breast cancer. Ben Venue was the sole worldwide supplier of Doxil, which is now unobtainable.

Fox says most people don’t realize how decrepit many U.S. drug plants are, especially those that make generic drugs.

Ben Venue Laboratories says it has invested more than $250 million over the past three years to upgrade its facilities, “and continues to invest millions more in order to restore production as quickly as possible.”

The FDA says the methotrexate crisis may be narrowly averted because the agency has persuaded to ramp up production of preservation-free injectable methotrexate.

Brenda Carr’s 4-year-old daughter, Rowen, is a leukemia patient at Children’s Hospital and Clinics of Minnesota.

“What I just couldn’t believe was that there was nothing really to prevent this from happening,” Carr says. “It gets really frustrating. I try to stay logical about it, but, unfortunately, I’m a mom.”

Doctors inject methotrexate directly into the spines of patients with ALL. For those with the bone cancer, they must use very high doses of the drug. In such cases, the methotrexate must be free of an alcohol-based preservative that is highly toxic at high doses. Otherwise, it could result in paralysis.

Carr says she has her fingers crossed. But she’s skeptical.

“This isn’t the first time we’ve been on the brink of drug shortages, especially in cancer treatments,” Carr says. “I don’t want another mom to have to be thinking about whether or not their child is going to get the medication they need.”

Experts say there certainly will be other parents who will have to worry about other shortages, because the root causes will not be easily resolved.

happening,” Carr says. “It gets really frustrating. I try to stay logical about it, but, unfortunately, I’m a mom.”

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  • I’m just waiting for the first wag to come along and claim that this is the government’s fault, rather than what it really is: a failure of the “free market.”

  • Dean:

    Actually, it is some of both. The FDA’s oversight of pharmaceutical labs and plants has been shabby.

  • RP

    It’s time for the government to require all large drug companies to produce some of the drugs that have a low demand, but a high need for each specific illness.

    That needs to be part of the Affordable care act and that would eliminate the problems with shortages should one company have manufacturing problems.

  • RP:

    This makes great sense. It cannot be part of the Affordable Care Act because that train already has left the station, but perhaps — perhaps after Obama is re-elected he can revisit the fight against Big Pharma and propose legislation that would obviate shortages, which in my view are often driven by proprietary concerns (like profits).

  • STinMN

    It isn’t just the FDA and those profit hungry pharmaceutical companies that are causing the shortage. It is also the suppliers of the precursors needed to product the pharmaceuticals that are limiting supply.

    My neighbor works in production control for a local generics pharmaceutical company. They were recently mentioned as one company that had stopped producing a low cost drug. My neighbor has been in the hot seat since because that is the line he works on. The biggest reason they don’t product the drug? It’s not the lack of profits, he said it is actually one of their more profitable products in a generics market with razor thin profits. They don’t make the drug because they can’t get the raw materials. Those other, more profitable drugs from the huge pharmaceuticals use many of the same precursors, and those manufacturers are willing to pay much more to lockup the supplies. My neighbor’s company has resorted to buying on the open market since their contract purchases don’t get delivered. Many of these suppliers won’t deliver once they learn the materials will be used for pharmaceuticals. They are too afraid of any liability that could be involved.

  • Commenters here point to something that hasn’t been mentioned here: the current regulatory pricing environment has made it impossible to manufacture a number of these drugs without taking a massive loss. (Short version: many drugs can’t legally be bought directly by patients, and Medicaid and Medicare won’t pay what it costs to make these drugs anymore, although it used to.)

    This would almost certainly explain part of what happened here; although it would not excuse allowing a factory to deteriorate to such dangerous levels, we should not be surprised if we’ve created a system wherein these drugs are routinely sold at a loss, which will inevitably cause some companies to stop making them and less ethical companies to cut corners to dangerous levels.

    This piece in the New York Times does a good job of getting to the meat of the matter, which is that recent reforms have made it impossible to sell these drugs in a way that even covers the cost of manufacturing them (i.e. even made on a non-profit basis it would not be possible).

    This is a call for regulatory reform but it looks like that will be tough in an environment where you have one set of people screaming that it’s evil to expect anyone to make a profit on medicine and another saying that government involvement is everywhere and always evil.

  • STinMN:

    I’m not buying what your neighbor tells you. That would be like Apple saying it can’t make iPhones because it can’t get the high-impact glass for the touch screens or GM can’t make cars because it can’t get the steel.

    Where there is a will there is a way, and I would suggest that you neighbor works for a lazy management.

  • STinMN

    Wrong analogy Shawn. More like Apple buying up the 10.1″ LCDs prior to the iPad release, enought that they prevented others from getting them.

    I know from my own experience in the medical device industry that supply constraints are real and can kill companies. One I worked made a device that used injection molded polycarbonate components. We owned our own presses couldn’t produce the device because we couldn’t secure enough USP polycarbonate, all available supplies were already locked up by the larger medical device manufacturers. The company eventually went under in no small part because of this.

    A former co-worker started his own medical device company. He had come up with a very novel surgical product based on a dissolving polymer. They had no issues with the raw materials needed to build the product until they published their clinical trials results. Suddenly they couldn’t get any of the required polymer, their usual supplier had their annual production purchased by a major device manufacturer. Other suppliers they had used also had their production purchased by the same device manufacturer. The board eventually sold the business to this device manufacturer at a much lower price than the company was probably worth, in no small part because they couldn’t build the device without the polymer.

    The company my neighbor works for invested in their own purifying facility so they could make their own USP grade chemical, but suppliers are unwilling to sell them the industrial grade feedstock due to their fear of liability I suppose this is a sign of lazy management.

    For small manufacturers in the medical industry raw material supply constraints are just one of many issues they need to deal with. But I’m sure it is just signs of lazy management.

  • I am largely on STinMN’s side here; though I don’t know for sure that this is what’s going on in this case, it is absolutely true that large corporate entities will often lock up all the available supply of raw materials that smaller companies need to stay stay viable. Furthermore, as the New York Times article I linked notes, the small manufacturers of these generic drugs are in desperate straits–left/liberals should remember that “the drug companies” are not one entity, and there are a lot of small-time players producing generic drugs. If these small-time players get financially devasted, they aren’t going to be able to produce the cheap drugs–which is very much in the interest of the Pharma Giants, who want you buying their patented expensive drugs instead of the cheap generics.

    One of the things a functional regulatory environment is supposed to do is prevent large corporate players from doing this to small enterprises, but the current “government is always bad” mentality that is so pervasive on the Right would seem to prevent us from doing so. The left/liberal answer isn’t very helpful either, since simply bashing the producers of cheap generic drugs and demanding that they operate at a loss doesn’t do anything at all to help.

    This is one of the problems with the current environment where conservatives and liberals are more concerned with talking at each other rather than with each other, bashing each other rather than trying to find areas of common ground with each other.

    If you want a fascinating dichotomy, look at this discussion versus the same discussion of this very issue over at Dean’s World, where my conserva-libertarian pals are all arguing that the government caused this mess with lousy regulations, while you guys over here are mostly arguing that the whole problem is the drug companies’ fault. One of them even notes that of the drugs produced by that plant that was shut down, there was no evidence that they had actually produced any contaminated drugs. Specifically, “Testing has since shown that it was of acceptable quality and the FDA has now cleared it for release, the company said Wednesday.”

    Thus the issue of low availability of these drugs appears not to be a simple matter of “drug companies bad” or “government bad,” but a dysfunctional regulatory environment. But guess what? It’s really hard to fix these things if people on both sides won’t talk to each other and try to arrive at practical solutions. When ideology trumps common sense we all lose.

  • Rcoutme

    The last good FDA commissioner that I remember was David Kessler. He was brought in after the 1980’s scandals. He made enemies quickly in Washington and was eventually pushed out during the Clinton/Republican Congress years. He knew what he was doing–that was a threat to some of the pharmaceutical company executives.

    I worked in pharmaceuticals until I became disabled. I was an analytical chemist. As a consequence, I was deeply involved in the regulatory aspects of things. If you think that the SEC had a revolving door–you should see what happened at the FDA. A scientist could almost write his own ticket if he spent a few years at the FDA.

    In the generic section (which is what the article is talking about), the ‘razor thin’ profits are all that these companies have. If a drug is not profitable, they CAN NOT produce it. Mandating such action would simply cause the company to shut down. So, if the laws state that Medicare, Medicaid or whatever has to pay for it and won’t pay enough, then it won’t be made. That is the nature of business.

    Meanwhile, plants falling into disrepair are likely due to the FDA getting bashed on a constant basis by lawmakers (many of whom claim that they want to abolish the agency–even though it pays for itself!) There should never have been a relaxing of the ban on advertising Rx drugs. There should never have been an allowance that companies could sell supplements with outrageous claims without prior FDA clearance of proof.

    The pro-business, anti-regulation crowd has caused the above tragedy. It is not the fault (or not fully) of the company involved. If they had had a pattern of investing more in their factories, they would likely have gone bankrupt. Meanwhile, the dog-eat-dog world of generic pharmaceuticals mandates that you get the product out with the absolute lowest cost.

    Instead of trying to get the cost to a reasonable level, we leave it to the ‘market’. The market will get the shoddiest product available, provided that the payer is not the user. It will do the same if generics are ‘mandated’ by state law (as happens in many states) without regard to the quality of the product.

  • TheMagicalSkyFather

    Oddly the true advantage of a single payer system is that their is central planning for what in reality finite resources. I do not see how even an utterly unregulated market would help with a problem of finite resources IF we actually want healthcare to save lives and ease/minimize human suffering.

    If on the other hand we just want to make money and let god sort out the dead and dying then regulation is evil and the healthcare market is the best thing since sliced bread. I tell you that it will cost X amount to save your loved one and otherwise they die and oddly just like when the mafia says the same you will find the money, of course all other sectors of the economy will merely be things to be bargained off to pay for the lives of those we love though. The downside of gunboat capitalism “give me money or someone dies” is that it hollows out all other sectors because we as a species have an odd habit of not wanting our loved ones to be in crippling pain or die.

    Of course in a “free market” this would be the norm, it is not a companies problem that they failed to save a life it is only their job to make a profit…if they failed to make a profit then we have a problem. A single payer system would mostly just give the advantage of a central person/group to blame that it would benefit to make changes to ensure it doesnt happen in the future. Of course that fails to work once a profit comes into the mix since what if doing the wrong thing makes you more money, what if it makes you incredible amounts of more money?

  • Rcoutme

    Well…it is not about making obscene profits. Why do you suppose that there is only one supplier? Hint: it’s not because the sole manufacturer is making so much money that they can’t store the paper in warehouse! If a business loses money on a product but keeps on selling it (without some reasonable expectation of a turn-around), a competitor will start making all the other products BESIDES the losing one and put the first company out of business. Like it or not, that is capitalism.

    Mandating that a company produce at a loss is an Ayn Randian nightmare. You may not like her politics, her lifestyle, her philosophy, etc, but she was dead-on accurate about some things. That was one of them. You CAN NOT ask a company to produce a product at a deliberate loss! They can’t stay in business that way! If you are so concerned about having this medication available, why don’t you go create a pharmaceutical company with the sole purpose of creating that drug?

    What? You either don’t have the money to do this or consider it a bad investment? But hey! Think of the poor children! Just because Medicare and Medicaid mandate that you make the stuff at a loss is no excuse for not creating that business, right? I mean, we should all be locked up or sued for millions of dollars for not, each and every one of us, creating pharmaceutical companies to provide medicines for people, while having operational losses, right?

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