We were interviewed a few days ago for an article published in Business Insurance News and asked for our thoughts about the future course of the fungal meningitis litigation. What follows is an elaboration on our published comments.
With the death toll at 28, and with 377 confirmed cases of meningitis (plus nine other cases of peripheral joint infection) among those who received what was supposed to have been a parenteral compounded sterile preparation (CSP), it’s hard to see how the compounder, NECC, could possibly satisfy the claims that will be brought. The task then for the plaintiffs’ bar is to advance theories that will ensnare those entities and individuals who can. That means they’ll be trying to push liability down the line to distributors, hospitals and doctors; and, back up the line to the drug manufacturer. Depending on what the NECC witnesses say they may even try to push liability sideways and out to those who supplied the equipment and even consulting services to NECC regarding its operations including its clean room and terminal sterilization processes. So how might plaintiffs attempt to establish liability?
For those down the line they may allege 1) failure to warn; 2) failure to test; and, 3) failure to re-sterilize. For those up the line they may, as with the Teva cases we discussed earlier this year, allege negligent and/or defective packaging – i.e. failure to break the doses into the smallest possible units so as to effectively eliminate multiuse and, in large part, compounding, altogether. Finally, for those who provided either the hoods in which the originally sterile products were opened and compounded, the equipment for terminal sterilization or the advice about how to set up and run the processes used to make CSPs they may allege product defect and negligence. "Ok", you say, "but wasn’t this a one-off? A once-in-a-lifetime problem that can be laid at the feet of a rogue compounder?" Would that it were so.
Forty years ago hundreds and maybe thousands of Americans were killed as a result of just one wave of iatrogenic infections. See e.g. "Sepsis Caused by Contaminated Intravenous Fluids. Epidemiologic, Clinical and Laboratory Investigation of an Outbreak in One Hospital." And it has only been 10 years since the last time the CDC identified a compounding pharmacy as the source of meningitis cases due to contamination of the very drug at issue now – methylprednisolone. Add to that recent findings that (a) even experienced and well-trained compounders produce contaminated preparations more than 2% of the time (see "Aseptic Simulation Test Challenged With Microorganisms for Validation of Pharmacy Operators"), (b) bacteria have been demonstrated to feast on even some of the most toxic chemotherapeutic drugs; and, (c) just a handful of these promiscuous microbes can reproduce until they’re several billion strong in just 24 hours, and perhaps a duty to warn of the risks of receiving CSPs can be fashioned. To that end try on this quote: "To prevent further outbreaks, the people administering the agents must fully understand the ability of these drugs to support microbial growth so as not to put the patients at risk", from "Bacterial Contamination of an Anesthetic Agent".
What about advocating a duty to test or re-sterilize CSPs on the part of those who distribute or administer them? This course looks less promising at first. Because of the chronic problem of iatrogenic infections due to CSPs, compounding pharmacies have been subject to strict regulation since 2008 under USP chapter 797. Their processes, particularly their clean rooms, testing and sterilization procedures, appear to be explicitly designed so that those who administer compounded drugs can rely on their warranty of being "sterile". Furthermore, opening sealed vials for testing or demanding that everyone down the chain of distribution have gamma radiation sources (which in some cases may damage the medicine being sterilized) to re-sterilize the product would either compound the problem (no pun intended) or create new ones.
On the other hand, an argument may perhaps be made for further testing or re-sterilization along the following lines: hospital compounding pharmacies and satellite compounding pharmacies are already responsible for far more cases of morbidity and mortality than the NECC-related fungal meningitis outbreak. The difference is that they tend to do it onesies or twosies-style – a pertinent quote being: "Finally, we must recognize that iatrogenic infections happen daily in our hospitals and other health care settings with much less media attention, and we must continue to invest daily in careful and insightful infection control policies to prevent, limit, and manage them."
So what about pushing liability back up the chain? This looks to be the least viable route. The successful claim in the Teva cases referenced above was to the effect that the company had facilitated the transmission of a pathogen (specifically hepatitis C) from an infected patient to multiple uninfected patients by selling its drug, propofol, in (potentially) multidose vials which were used to dose multiple patients – despite the fact that the physician who directed such use was blatantly violating the CDC’s Standard Precautions which prohibit the use of multidose vials for more than one patient. The idea was that packaging parenterals in single dose vials (SDVs) was a simple and obvious solution to an obvious problem. The reality is that SDVs may not make any difference.
Dosing for most medicines isn’t like setting the size for an aspirin tablet. Instead there’s often a "Goldilocks effect" whereby only a certain and very precise dose, calculated on the basis of patient-specific parameters, does any good. Too much or too little is worthless or worse. That means that unless a manufacturer offers a nearly infinite range of doses the result is usually waste because not all of the contents of the vial are used, or all of it plus only a bit of another are needed. SDVs are then, in the eyes of many, a waste of money and, in the case of very expensive small batch drugs, a waste of lives. And the value of unused drugs discarded due to SDV rules is said to be approaching $1 billion annually. Furthermore, SDVs may also lead to more mixing and prep time in certain operations (all of which increase the risk of contamination) than might otherwise have occurred had larger quantities been available – see e.g. "Invasive Staphylococcus aureus Infections Associated with Pain Injections and Reuse of Single-Dose Vials – Arizona and Delaware, 2012". Therefore, imposing a duty on pharmaceutical companies to package drugs only in the quantity actually needed by each future patient (the only way we can think of to cut out the compounder) would seemingly put them in an impossible situation – damned if they don’t package the drug in a standard SDV size and damned if they do – and, as demonstrated by the outbreak involving the reuse of SDVs, either way it would likely make no difference as the limitation SDVs seek to impose is easily wired around by lab technicians.
As for liability claims against those who provided NECC products or consulting for its clean room and sterilization devices and procedures we expect that to be a largely fact-driven issue turning on how and where the contamination originated in the process.
However it turns out we predict that these recent fungal meningitis cases are just the tip of a very big iceberg. Have a look at "Is There A Need For Autopsies In The Management Of Fungal Disease". An awful lot of people are dying of fungal CNS infections that nobody detects unless an autopsy is performed.
And while most of the cases reported in that and similar papers involved people with impaired immune systems an increasing number of fungal meningitis cases are being detected in immunocompetent individuals. Add to that the very interesting factoid that the case of meningitis that triggered the discovery of the current meningitis outbreak was caused by a strain of Aspergillus fumigatus not found in any of the recalled vials nor in any other patient – the rest due almost exclusively to Exserohilum rostratum which was found in recalled vials. Top it off with this afternoon’s news that Bacillus species have been found in two other CSPs distributed by NECC and you have to wonder whether (a) the discovery of the fungal meningitis outbreak wasn’t pure serendipity because the index case, a patient with a longstanding history of degenerative back pain, may well have gotten his infection as the result of some prior medical intervention but just happened to manifest symptoms and die after receiving an injection of the NECC CSP; and, (b) there aren’t therefore a whole lot more deaths attributed to stroke, etc that are in fact due to undetected iatrogenic infections.
In coming days we’ll put something up on the defenses to plaintiffs’ expected claims.