April 22, 2020

Pandemic highlights need for pragmatic clinical trials


Now more than ever we can benefit from studies embedded in health-care systems to answer common clinical questions

By Greg Simon, MD, MPH, senior investigator, Kaiser Permanente Washington Health Research Institute and psychiatrist, Washington Permanente Medical Group

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 address clinical questions that arise routinely in health care settings worldwide.  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 much more urgent than we could have imagined.

Leaving aside heated debates regarding effectiveness of hydroxychloroquine or azithromycin, we can point to other practical questions regarding use of common treatments for people at risk for COVID-19.  Laboratory studies suggest that ibuprofen could increase binding sites for the coronavirus that causes COVID-19. Should we avoid ibuprofen and recommend acetaminophen for anyone with fever and respiratory symptoms?  Acetaminophen toxicity is not benign. Laboratory studies also suggest that ACE inhibitor medications, among the most common medications for hypertension, could increase coronavirus binding sites. Should we recommend against use of ACE inhibitors for the 20 percent of older Americans now using them daily?  Stopping or changing medication for hypertension certainly has risks. Laboratory studies can raise important 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, involving typical patients and typical clinicians, and study the way treatments work under real-world conditions. Compared with traditional clinical trials, which are done in specialized research centers with extensively screened patients under highly controlled condition, pragmatic trials are both more efficient (we can get answers faster and cheaper) and more generalizable (the answers apply to real-world practice). 

While traditional controlled clinical trial may be best for research on an experimental intervention such as a new drug versus a placebo, pragmatic trials are designed to study interventions already used in 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.  Traditional controlled 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 support common and consequential clinical decisions. Clinicians want to inspire hope and confidence. Patients and families making decisions about health care 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 has used 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 though Michael’s ethnic joke does not truly apply, 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?” A pragmatic clinical trial is likely to be the best solution.

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