Adrian Hernandez, Rich Platt, and I recently published a Perspective in New England Journal of Medicine about the pressing need for pragmatic clinical trials to answer common clinical questions. We started writing that piece last summer, long before any hint of the COVID-19 pandemic. But the need for high-quality evidence to address common clinical decisions is now more urgent than we could have imagined.
Leaving aside heated debates regarding the effectiveness of hydroxychloroquine or azithromycin, we can point to other practical questions regarding use of common treatments by people at risk for COVID-19. Laboratory studies suggest that ibuprofen could increase virus binding sites. Should we avoid ibuprofen and recommend acetaminophen for anyone with fever and respiratory symptoms? Acetaminophen toxicity is not benign. Laboratory studies suggest that ACE inhibitors, among the most common medications for hypertension, could also increase virus binding sites. Should we recommend against ACE inhibitors for the 20% of older Americans now using them daily? Stopping or changing medication for hypertension certainly has risks. Laboratory studies can raise those questions, but we need clinical trials to answer them with any certainty.
Pragmatic or real-world clinical trials are usually the best method for answering those practical questions. Pragmatic trials are embedded in everyday practice, involve typical patients and typical clinicians, and study the way treatments work under real-world conditions. Compared to traditional clinical trials, done in specialized research centers under highly controlled conditions, pragmatic trials are both more efficient (we can get answers faster and cheaper) and more generalizable (the answers apply to real-world practice).
Pragmatic trials are especially helpful when alternative interventions could have different balances of benefits and risks for different people – like ibuprofen and acetaminophen for reducing fever. Laboratory studies – or even highly controlled traditional clinical trials – can’t sort out how that balance plays out in the real world.
In our perspective piece, we pointed out financial, regulatory, and logistical barriers to faster and more efficient pragmatic clinical trials. But the most important barrier is cultural. It’s unsettling to acknowledge our lack of evidence to guide common and consequential clinical decisions. Clinicians want to inspire hope and confidence. Patients and families making everyday decisions about healthcare might be dismayed to learn that we lack clear answers to important clinical questions. We all must do the best we can with whatever evidence we have, but we should certainly not be satisfied with current knowledge. If we hope to activate our entire health care system to generate better evidence, we’ll probably need to provoke more discomfort with the quality of evidence we have now.
Inadequate evidence can also lead to endless conflict. My colleague Michael Von Korff used to use the term “German Argument” to describe people preferring to argue about a question when the answer is readily available to those willing to look. Michael was fully entitled to use that expression, since his last name starts with “Von.” Germany, however, now stands out for success in mitigating the impact of the COVID-19 pandemic. Even if Michael’s ethnic joke no longer applies, the practice of arguing rather than examining evidence is widespread. The best way to end those arguments is to say “I really don’t know the answer. How could we find out as quickly as possible?”