**Update, the NYT has an editorial in their Sunday edition recommending the passage of two bills in congress requiring advanced notice from drug manufacturers in event of likely shortage.
Health affairs discusses the increasingly frequent shortages of critical, life-saving, generic drugs. This is a serious problem that seems mostly limited to the U.S. healthcare system, and may adversely affect you or someone you know.
Many of the same drugs are not in such short and unpredictable supply in Europe, where in some cases they carry higher prices. This provides one major clue to the root cause: It’s the money.
Three of every four drugs on the US government’s shortage list were sterile injectable drugs, according to a report by HHS. For the most part, these are relatively low-cost generics. Simply put, most of those drugs are not very profitable to produce and sell, or supplies of them would not have dried up.
At an online presentation for journalists in November, Valerie Jensen, associate director of the FDA’s Drug Shortage Program, provided a casebook example. She mentioned the price of the tried-and-true sedative propofol, a lethal dose of which was found to have caused the death of singer Michael Jackson: The cost is forty-eight cents for a twenty-milliliter vial. “The older, sterile injectables are not economically attractive” for manufacturers to produce and market, Jensen said. Other generic drugs can have higher profit margins.
Propofol, one of the most frequently used drugs by anesthesiologists, is in increasingly short supply. I get emails from my hospital about which drugs are in short supply as physicians then try to ration these drugs for the most critical cases. In my own experience in the last year I’ve seen shortages of everything from injectable calcium gluconate (for electrolyte deficits), to levophed (a life-saving pressor used in critical care), metoclopramide (anti-nausea), and fentanyl (a powerful and useful short-acting narcotic). The FDA has a full list of recent shortages and it’s scary. Parents are having trouble finding drugs for their kids’ ADHD, vital chemotherapeutics like daunorubicin and doxorubicin are in short supply, dexamethasone (a powerful steroid), valium, digoxin (a staple of congestive heart failure and anti-arrhythmic treatment), diltiazem (hypertension and anti-arrhythmic), phenytoin (anti-epileptic also often used in acute brain injury), furosemide (an ubiquitous diuretic), haloperidol (anti-psychotic and sedative), isoniazid (a antibiotic used in TB), ketorolac (an excellent anti-inflammatory and analgesic), levofloxacin (a quinalone broad spectrum antibiotic), methotrexate (immune modulator), midazolam (a great short acting sedative), naltrexone (for reversing opioid overdose), vasopressin (another pressor) all are in short supply.
The drugs affected span all classes, what they have in common is they are all generic. Since there is too much competition in generics and too little profit margin, drug companies do not have a financial incentive to maintain adequate stocks to keep the drugs cheap and available. Shortages, if anything, increase profits because then the prices become artificially inflated.
Manufacturers, not surprisingly, blame the FDA, however the FDA hasn’t changed its standards despite increasing problems with shortages due to contamination or impurity. And that’s just for manufacturers in this country, fully 80% of the medications are produced, or active ingredients are produced, abroad. The main problem seems to be a concentration of production to a handful of companies that have adequate production capacity to compete in the generic market:
There is also a high level of concentration in US manufacturing for such drugs. That leaves little redundancy in the market as there would be for, say, generic statins. Three companies in particular–Hospira, Teva, and the Bedford Laboratories division of Boehringer Ingelheim–have been involved in selling 71 percent of the sterile injectable market by volume, the government says.7 All three have had manufacturing problems in the past two years.
With such consolidation as well as tight inventory management practices, the specialized manufacturers of injectable drugs lack the flexibility to adapt to manufacturing disruptions. If one plant shuts down, it may overburden the limited remaining competitors or choke off the supply entirely.
It’s hard to estimate the effects of these shortages, I don’t have good data on the damage done nationwide, only my personal experience. In particular, I remember during an ICU rotation running out of levophed, an incredibly important pressor that helps patients who are in shock from becoming fatally hypotensive.
Shock is when there is evidence of end organ damage due to inadequate tissue oxygenation. It can be from blood loss, infection, severe neurological injury, cardiac failure, or anaphylaxis. When people are in septic shock, for instance, the body’s response to the infection is excessive, fluid pours out of blood vessels and into the tissues due to the release of inflammatory cytokines and capillary beds vasodilate as shock progresses leading to circulatory collapse. The patients can’t keep enough fluid in their vessels to continue to perfuse their organs. The mainstay of treatment is first fluids to replace the lost intravascular volume, but if severe, it’s often necessary to use pressers to keep up cardiac output and maintain vascular tone so the resulting hypotension doesn’t cause multi-system organ failure. Levophed (or Norepinephrine) is often the first-line pressor.
We have alternative drugs, at the time we used dopamine, which used to be the most commonly used presser before levophed. But it’s not as commonly used today even if still considered a first line medicine in severe septic shock. It can’t quite replace levophed, studies show fewer people respond to dopamine as they do to levophed and has different physiologic effects at different doses. At low doses it doesn’t have a significant pressor effect, but at intermediate and high doses it does. However, if you go too high the vasoconstriction becomes dangerous and you may see a drop off in kidney function. It was an interesting couple of weeks, and I began to miss levophed. I don’t think anyone was harmed by the loss but I definitely felt the drug was inferior, often requiring addition of a second pressor to obtain an effect, and given enough patients diverted to the drug I imagine you’d eventually see a negative effect.
We were lucky that we had alternatives, but for some patients there may not be a simple alternative drug to replace what they need, for instance chemotherapeutics in oncology:
The FDA and the American Hospital Association say that the shortages have already caused thousands of cancer patients to delay treatment and nearly every hospital to ration supplies or turn away new patients. Howard Koh, the HHS assistant secretary for health, said at a House hearing in September 2011 that hundreds of clinical trials have had to be halted or delayed for lack of drugs.
And the lack of anesthetics has cause cases to be cancelled, as well as poorer outcomes reported by anesthesiologists. Not to mention the problem of having to re-familiarize doctors with medications rarely used or outmoded by superior drugs for decades. One of the reasons we train for so long is because medicine is a practice. If you haven’t practiced with these medications you will be less familiar with their dosing, their side-effects and toxicities. And not just the doctors but the nurses and pharmacists as well will be less familiar with more rarely used medications.
Then there are the scalpers and gougers:
An online survey last year found 56 percent of 549 hospital purchasing agents and pharmacists reported receiving daily solicitations from gray-market sellers, and most bought drugs from them.9 “It is unreal to have to deal with ‘scalpers’ in health care,” one survey respondent said. In one case, a supply of propofol cost $25,000 instead of $1,500.
Another survey–in August, conducted by the Premier Healthcare Alliance, a group of more than 2,500 US hospitals and 80,000 other medical sites–found an average markup of 650 percent from contract prices, although some of the distributors challenged the survey.10 The profiteers are generally not believed to be responsible for the shortages but merely to be capitalizing on them–and spawning congressional and Department of Justice investigations.
Clearly there are problems with the profit-margin on generics. The result is manufacturers try to cut costs where they can, they export production abroad (and away from FDA oversight), and keep supplies low. Since so many shortages are due to contamination and impurity this certainly suggests decreased regulation is not the answer. We need to maintain stringent standards for drug quality. But de-regulation is not the only intervention to influence a market, and when it comes to pharmaceuticals it should be the last resort as we have evidence that defective drugs are being manufactured and deflected from the market by adequate FDA oversight.
So how can we resolve this problem? Currently the FDA is supposed to be warned within 6 months of an impending shortage so that alternative supplies may be found, but shortages due to contamination/impurity, sudden closings of factories, and unexpected loss of smaller manufacturers supply show that this system is ineffective. We need a better warning system for impending failures of the supply chain. Further we need to create economic incentives for manufacturers to produce adequate supplies of drugs that may have low profit margins, and to continue to produce drugs for rare diseases and chemotherapeutics. Allowing manufacturers a tax write-off for costs of maintaining an overstock of critical medications, or for producing critical cancer therapeutics might be in order. Increasing medicare disbursements on generic medications would also help, but both of these interventions will probably cost a lot of money. The alternative might be worse. Lives lost due to critical drug shortages. In the end medicine and medical care is not free. We are a capitalist society and medical manufacturing is a for-profit enterprise. Right now that enterprise is failing our patients, and before a larger crisis is spawned by this failure we have to acknowledge that generics are a critical component of health care, are cost-effective compared to drugs under patent, and generic manufacturing needs to be encouraged and supported in this country.