Regulators, polypharmacy and medical errors: what’s the story?
Polypharmacy, being on multiple different medications, is becoming more common. This is partly the result of an aging global population but also because more medications are available to treat more conditions. However, there is a downside. With more medications, there is more chance of an interaction between those medications — and that can be seriously dangerous.
What’s the risk?
It is hard to provide precise figures for how dangerous. The US Institute of Medicine estimates that around 7000 deaths annually are from adverse drug reactions because of medical errors. However, other estimates put the figure much higher.
How many of these adverse reactions are the result of interactions between drugs? Studies suggest that drug interactions cause around 3%–5% of preventable in-hospital adverse drug reactions. They are also an important contributor to visits to emergency services and hospital admissions.
The rate of adverse drug reactions increases exponentially among people on four or more medications. It is therefore important to understand how drug interactions work, to make appropriate prescribing choices. That’s where medical regulators come in.
The role of regulators
Regulators have a key role in approving new drugs. Broadly speaking, pharmaceutical companies submit evidence to regulators that a new drug is safe, and regulators decide whether to approve the drug for use.
That, however, is not the end of the story. Most new drugs are approved based on relatively small-scale clinical trials, involving an average of 1,500 patients and lasting a relatively short time. It can be difficult to detect rarer adverse events. Trials also tend to select the less complicated patients, to make the effect of the drug more obvious. That largely rules out anyone with polypharmacy being involved — and that means that many drug interactions do not show up until much later. Ongoing regulatory involvement is therefore crucial.
Consider a drug called bromfenac, a non-steroidal anti-inflammatory drug that was removed from the market in 1998. You may not have heard of it, because it was available for less than a year. It caused serious hepatotoxicity in around one in 20,000 patients who took it for more than 10 days.
This did not show up in clinical trials, because the numbers were just too low. The problems only emerged because doctors reported these adverse drug reactions to the US Food and Drug Administration (FDA). Reports of adverse drug reactions allow regulators to decide whether drugs should continue to be available, the conditions of their license should be varied, or they should be withdrawn.
Unfortunately, there are some serious misconceptions about adverse drug reactions that mean that many are not reported. Many medical professionals still believe that all serious adverse drug reactions are known before a drug is marketed — and as we have seen, this is clearly untrue. Other people do not believe it is worth reporting because one physician’s report is unlikely to make any difference. This too is untrue: the FDA has documented several occasions where one report was enough to start an investigation. Second, each ‘one physician’ adds up to create a much bigger picture.
Regulators vs. pharma?
Pharmaceutical companies want to get drugs onto the market and regulatory approval is a key barrier. This makes it sound a bit like regulators vs. pharma. However, regulators want to approve new drugs — provided they are safe and beneficial to patients. If possible, they will avoid withdrawing licenses, and instead warn prescribers about problems, and advise on conditions for prescription.
Problems arise when this process breaks down. In a training module, the FDA highlights four drugs — terfenadine, mibefradil, astemizole, and cisapride — whose use was removed or restricted. This action was taken very reluctantly, and only after both regulators and manufacturers had already warned prescribers about possible drug interactions. To quote the module:
“[The FDA’s inability] to effectively warn health care providers and patients about drug interactions and … to translate existing knowledge into changes in prescribing have resulted in huge economic consequences for the pharmaceutical industry and the loss from the marketplace of effective drugs.”
A fine balance
Trying to reduce polypharmacy is important. However, for many patients, this cannot always be done safely. It is therefore crucial to understand the basis for drug interactions, and prevent them wherever possible. Regulators play a key role in this. They collate and analyze information about adverse reactions, then disseminate this to medical professionals and pharma companies to inform prescribing decisions. In this complex situation, everyone, including regulators, has a role to play in increasing patient safety in the context of polypharmacy.
