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

Lost in Translation: Google’s Translation of Palliative Care to ‘Do-Nothing Care’

by: Cynthia X. Pan, MD, FACP, AGSF (@Cxpan5X)

My colleagues often ask me: “Why are Chinese patients so resistant to hospice and palliative care?” “Why are they so unrealistic?” “Don’t they understand that death is part of life?” “Is it true that with Chinese patients you cannot discuss advance directives?”

As a Chinese speaking geriatrician and palliative care physician practicing in Flushing, NY, I have cared for countless Chinese patients with serious illnesses or at end of life.  Invariably, when Chinese patients or families see me, they ask me if I speak Chinese. When I reply “I do” in Mandarin, the relief and instant trust I see on their faces make my day meaningful and worthwhile.

At my hospital, the patient population is about 30% Asian, with the majority of these being Chinese. Most of these patients require language interpretation.  It becomes an interesting challenge and opportunity, as we often need to discuss advance directives, goals of care, and end of life care options…

Elderhood: Podcast with Louise Aronson

In this week's podcast we talk with Louise Aronson MD, MFA, Professor of Geriatrics at UCSF about her new book Elderhood, available for purchase now for delivery on the release date June 11th.

We are one of the first to interview Louise, as she has interviews scheduled with other lesser media outlets to follow (CBS This Morning and Fresh Air with Terry...somebody).

This book is tremendously rich, covering a history of aging/geriatrics, Louise's own journey as a geriatrician facing burnout, aging and death of family of Louise's members, insightful stories of patients, and more.

We focus therefore on the 3 main things we think our listeners and readers will be interested in.

First - why the word "Elder" and "Elderhood" when JAGS/AGS and others recently decided that the preferred terminology was "older adult"?

Second - Robert Butler coined the term ageism in 1969 - where do we see ageism in contemporary writing/thinking?  We focus on Louise's…

Psychedelics: Podcast with Ira Byock

In this week's podcast, we talk with Dr. Ira Byock, a leading palliative care physician, author, and public advocate for improving care through the end of life.

Ira Byock wrote a provocative and compelling paper in the Journal of Pain and Symptom Management titled, "Taking Psychedelics Seriously."

In this podcast we challenge Ira Byock about the use of psychedelics for patients with serious and life-limiting illness.   Guest host Josh Biddle (UCSF Palliative care fellow) asks, "Should clinicians who prescribe psychedelics try them first to understand what their patient's are going through?" The answer is "yes" -- read or listen on for more!

While you're reading, I'll just go over and lick this toad.

-@AlexSmithMD





You can also find us on Youtube!



Listen to GeriPal Podcasts on:
iTunes Google Play MusicSoundcloudStitcher
Transcript
Eric: Welcome to the GeriPal Podcast. This is Eric Widera.

Alex: This is Alex Smith.

Eric: Alex, I spy someone in our …