Evidence-based Medicine in Disguise: Beware the Surrogate!

In this post, I will give ordinary folks a ‘peek behind the academic curtain’. I am not an academic physician, but a mere practicing gastroenterologist who spends my days ‘enlightening’ Cleveland colons. Why do some medical studies, which achieve breaking news status, often fall so short of our expectations? Physicians are cynical about these medical milestones, since they are often short-lived. Today’s cure may become tomorrow’s disease.

A common practice and serious flaw in medical research is to rely upon a surrogate marker when studying a disease. Let me explain. If you endure the following few paragraphs of literary driftwood, you will understand press reporting of medical studies on a deeper level.  This could directly affect your medical care and generate some interesting conversations during your next doctor visit.

A surrogate marker is an event or a laboratory value that researchers hope can serve as a reliable substitute for an actual disease. A common example of this is blood cholesterol levels. These levels are surrogates, or substitutes, for heart disease. If a medical study demonstrates that a medication can lower cholesterol level 10%, then we assume that this will also lower the risk of cardiovascular disease. Why doesn’t this same study determine if an anti-cholesterol drug decreases heart attack rates directly? After all, most folks would rather be spared a heart attack than have a silent decrease in their blood cholesterol levels.

Why are Surrogates Used?

It is much easier and cheaper for researchers to measure surrogates than actual disease events. What could be simpler than measuring blood cholesterol levels? In contrast, it would be a very tough slog to show that a cholesterol-lowering drug reduced heart failure or mortality rates. With a surrogate, medical studies can be completed much more rapidly, in contrast to studying actual diseases, which can take a decade or more to complete. By then, the findings may no longer be relevant. Surrogate research is also much less expensive to perform.

Surrogate results have flashy marketing appeal because their findings can be expressed in catchy headlines that extrapolate the actual conclusions. Haven’t we all read headlines like this?

Research shows that new blood test can prevent cancer

Surrogate research is valid if the surrogate truly represents the disease. Often, this assumption is questionable or outright false. Not long ago, cardiologists were going gaga over the CRP (C-reactive protein) blood test as a surrogate marker for cardiac disease. This was great news for the ‘statin’ drug manufacturers who claimed victory when their medications reduced CRP levels, but did this really prevent heart disease? I wonder. Surrogates often take on a life of their own, far removed from the actual disease they represent. Patients shouldn’t care if their ‘surrogates’ are improving; their objective should be to prevent disease, feel better and live longer. Yet, we physicians have often convinced our patients that surrogate improvement means better health. Monitoring cancer blood tests called tumor markers illustrates this point well.

“Great news Mrs. Bedridden. Your cancer blood test improved 10 points!”

“Thank you doctor, but I still can’t walk.”

In my own field, gastroenterologists remove colon polyps with enthusiasm and zeal. Polyps are not diseases. They are surrogates for colon cancer. We hope and believe that when we remove pre-cancerous polyps that we are reducing your risk of colon cancer. Interestingly, there is no double-blind placebo controlled trial (the gold standard of medical research) that establishes that colonoscopy reduces colon cancer. Just because it sounds logical, doesn’t mean that it’s true. There have been medical studies, for example, that have described treatments that reduce arterial plaque, which is a surrogate marker and not a symptomatic disease. Most of us would welcome a treatment that reduces plaque, because we would assume that this would benefit us by preventing heart attacks and strokes. Assumption, however, is not science.

Those of us who have been reading journals for some time are skeptical before we celebrate the medical breakthrough of the day or week. What is sound medical dogma today may fade over time and become junk science. This is particularly true of surrogate studies, which are indirect by definition.

Those who earn their living and their reputations from medical research may have a different view on surrogacy than I do. Indeed, surrogate research is an important research tool, that can open important therapeutic avenues and stimulate additional research. We must be mindful, however, how easy it is to exaggerate their conclusions beyond the data. The public needs understand this issue. Think about this the next time you read a news flash that promises a medical miracle. Chances are that the miracle is a mirage.