What is a "surrogate outcome"? Why should you care?

The dictionary defines a surrogate as “something that replaces or is used instead of something else.” When the average person thinks of surrogate, the most likely thing that comes to mind is a surrogate parent or child.

Surrogates are widely used in medicine, and often with a less valuable role than a surrogate grandparent.

When a new treatment is proposed, the ideal way it is tested is with a controlled trial. A large group of patients with the condition needing treatment are randomly chosen to receive either the current standard treatment or the proposed new one. They are followed and how each group does is compared. If the new treatment is clearly superior, it will then be recommended for general use.

Controlled trials like this are expensive to prepare and conduct and are generally funded either by the National Institutes of Health or, more often, by the drug company hoping to market its new treatment. If the disease being treated is one that gets worse quickly, and if one of the two remedies is much better, the results may be evident quickly. If the disease normally progresses slowly and/or the difference between the two treatments is small, the trial may have to be conducted for many years. The longer the trial runs, the more it costs the sponsor. Hence, the surrogate outcome.

What do patients expect of a treatment? They want to live longer and feel better. Proving that a new drug accomplishes either of these things better may be difficult when the natural history of the disease plays out over many years or when the new drug is only slightly better. Trial sponsors are thus motivated to find a “surrogate outcome” that may show superiority quicker than outcomes valued by patients are found.

A recent example was the new Biogen drug Aduhelm, that was approved because patients receiving it cleared a marker of Alzheimer’s Disease better than those getting the placebo, even though there was minimal improvement in dementia. Cancer drugs are often approved because a blood marker of cancer or the size of a defect seen on an imaging test improves more than they do on another treatment.

IF these surrogates were proven to be a valid “marker” of feeling better or living longer, their use would allow results to be available sooner and at lower cost. Unfortunately, this is often not the case. Between 2006 and 2018, 62% of the 85 new cancer drugs the FDA approved were approved based on surrogate outcomes. While drug manufacturers are supposed to later provide data on the true outcomes of survival and quality of life, this is often not done. Of approved cancer drugs, only a minority subsequently were shown to improve survival. The FDA should demand that confirmatory trials be reported within a reasonable timeframe, such as 3-4 years after accelerated approval. If such trials were not done or reported, the drugs should no longer be paid for.

When your oncologist or neurologist suggests that a “new and improved” drug be used, ask them to tell you the basis for considering it to be improved. (And don’t forget to ask them how the side effects compare to older drugs as well!)

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