Skip to main content

Surrogate End Points in Drug Trials: Caveat Emptor

It seems like such a good idea.  Before a patient takes a new drug, they would like to know that it is going to improve a health outcome they really care about.  Will it make me live longer? Will it lower my risk of becoming disabled?

But the problem is that it often takes a long time for a study of a new drug to show that it has meaningful impacts on patient outcomes.  Enter the brilliant idea of surrogate outcomes.  A surrogate outcome is an outcome that is associated with the health outcome a patient may really care about.  For example, a patient may want to take a drug to reduce their risk of getting dementia or Alzheimer's Disease.  They may care so much about preventing dementia that they will even take a drug that gives them side effects.  But, it may take a pharmaceutical company years to conduct a trial to determine if a drug prevents dementia.

Surrogate endpoints seem like a brilliant solution to this problem.  We know that biomarkers such as amyloid, that is found on a brain scan, or tau protein, that is found in the spinal fluid, are associated with dementia.  A patient may not care about reducing their level of amyloid or tau protein in and of itself.  But, the theory is that a drug that reduces amyloid or tau should also reduce the risk of dementia.  It will take a lot less time to prove that a drug has an effect on biomarkers than to prove it has an effect on dementia.  Testing a drug and treating a patient on the basis of these surrogate markers makes it possible to bring a drug to market much more quickly.

Doesn't that sound great?  Well, as eloquently described by Svensson and colleagues in JAMA Internal Medicine, it may not be so great after all.  While surrogate endpoints sound good in principle, in practice they often do not work.  Not only do they not work, but there are numerous examples where reliance on surrogate end points had disastrous consequences and harmed patients.  Svensson notes several notorious examples in the e-table of the article.  For example :
  • Clofibrate reduced cholesterol in persons at risk for heart disease.  Lower cholesterol is associated with a lower risk for heart disease.  Unfortunately, patients who took clofibrate were more likely to die.
  • Encainide reduces the number premature heart beats (PVCs) is persons who have had heart attacks.  PVCs are strongly associated with a higher risk of death after a heart attack.  Unfortunately, patients who took encainide after heart attacks were much more likely to die.  It is estimated that encainide caused thousands of excess deaths.
  • Rosiglatazone lowers the glycohemoglobin level in persons with diabetes.  Diabetes is a risk factor for heart disease and lower glycohemoglobin levels indicate better diabetes control. Unfortunately, patients who took rosiglitazone had more heart attacks.
It is curious why there is so much enthusiasm for the use of surrogate end points in dementia drug trials when there are so many examples of how the use of surrogate endpoints in other diseases led to such awful public health outcomes.  Hopefully, history will not repeat itself.

by: Ken Covinsky (@geri_doc)

Comments

Popular posts from this blog

The Dangers of Fleet Enemas

The dangers of oral sodium phosphate preparations are fairly well known in the medical community. In 2006 the FDA issued it’s first warning that patients taking oral sodium phosphate preparations are at risk for potential for acute kidney injury. Two years later, over-the-counter preparations of these drugs were voluntarily withdrawn by the manufacturers.  Those agents still available by prescription were given black box warnings mainly due to acute phosphate nephropathy that can result in renal failure, especially in older adults. Despite all this talk of oral preparations, little was mentioned about a sodium phosphate preparation that is still available over-the-counter – the Fleet enema.

Why Oral Sodium Phosphate Preparations Are Dangerous 

Before we go into the risks of Fleet enemas, lets spend just a couple sentences on why oral sodium phosphate preparations carry significant risks. First, oral sodium phosphate preparations can cause significant fluid shifts within the colon …

Dying without Dialysis

There is a terrific article in this weeks Journal of Pain and Symptom Management by Fliss Murtagh of King's College in London about the epidemiology of symptoms for patients with advanced renal failure who die without dialysis.  This study is important because while we know that patients with advanced renal failure have a limited life expectancy and the average age of initiation of hemodialysis is increasing, we know little about the alternatives to hemodialysis.  Specifically, we know nothing about symptoms affecting quality of life among patients who elect not to start dialysis (so called "conservative management" - is this the best label?).  This article provides a terrific counterpoint to the article in last years NEJM showing that nursing home residents who initiated hemodialysis tended to die and decline in function (see GeriPal write up here). 

The study authors followed patients with the most advanced form of chronic kidney disease (the new name for renal failu…

Survival from severe sepsis: The infection is cured but all is not well

Severe sepsis is a syndrome marked by a severe infection that results in the failure of at least one major organ system: For example, pneumonia complicated by kidney failure. It is the most common non-cardiac cause of critical illness and is associated with a high mortality rate.

But what happens to those who survive their hospitalization for severe sepsis? An important study published in JAMA from Iwashyna and colleagues provides answers and tells us all is not well. When the patient leaves the hospital, the infection may be cured, but the patient and family will need to contend with a host of major new functional and cognitive deficits.

Iwashyna examined disability and cognitive outcomes among 516 survivors of severe sepsis. These subjects were Medicare enrollees who were participants in the Health and Retirement Study. The average age of patients was 77 years.

When interviewed after discharge, most survivors were left with major new deficits in their ability to live independently. …