Friday, May 22, 2020

Surrogate or real?

The dictionary defines surrogate as “a person appointed to act for another,” and to the general public probably the most common use is in terms such as surrogate parent

In medicine, it is common to have surrogate decision-makers, such as the parents of a minor child, or the spouse or child of a person who is incapable of making their own decisions. Such surrogate decision makers have all-too-often been put in the difficult position during the COVID-19 pandemic of making dread decisions such as whether to have a loved one put on a ventilator. It is very common for an elderly patient to undergo intensive care when they have asked this not be done, and researchers have also found that many surrogates’ wishes are not followed by the medical staff. It is always best, and Covid-19 has just underlined this, for a older person (or a person of any age with serious medical problems) to be sure their wishes regarding the trade-off between possibly life-sustaining care and comfort be explicit, in writing, and discussed with family.

I want to focus, however, on another form of surrogate – the use of “surrogate end points” to approve a new drug.

The gold standard for proving that a new treatment works, or works better than an existing one, is the controlled clinical trial. A large group of patients are randomly given Drug X or Drug Y, or, if there is no existing useful treatment, Drug X or a placebo. They are then followed until a pre-specified outcome occurs and the results of the two groups compared. As regular readers of these posts know, I am much more impressed with a trial that uses death as the outcome being measured. For many of the events reported, the definition is often fuzzy. The research group frequently establishes a committee to “adjudicate” whether an event occurs. You do not need a committee to decide if a patient is alive or dead.

From a researcher’s perspective, the problem with using death as the outcome is that to establish that one treatment is better than another may take a large sample followed over a long time unless the disease is rapidly lethal. Large trials over a long time are costly to perform.

Enter the “surrogate.” The trial of a cancer drug may use “shrinking of the tumor by 50% on CT scan” or “reduction of a biomarker (blood test)” as the outcome studied. While these MAY correlate well with outcomes of more value to the patient, such as lifespan or quality of life, they may not. More and more cancer drugs are now being approved by the FDA based on surrogate outcomes. A recent study published in JAMA Internal Medicine found only a very weak correlation between these end points and overall survival. While a drug approved on this basis is supposed to have further tests done that do track overall survival, in a large percentage these studies are never done. Since these new drugs are often very expensive and have many major side-effects, it appears that patients are often exposed to potential harm with minimal potential meaningful benefit.

So, when the latest “wonder drug” is suggested, be sure to ask just HOW wonderful it really is. The reported results may be “statistically significant,” but are they clinically significant? Can anyone tell you this treatment will make you feel better or live longer, or will there just be a meaningless "surrogate" improvement?

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