August 24th, 2012

Topol: The Clinical Trial World Is “Contrived”

I was intrigued by an email that touted a piece by Eric Topol. The startling headline: “Get Rid of the Randomized Trial.” Eric is one of the pioneers of the large, simple randomized trial and contributed many landmark studies that have shaped the practice of cardiology. His TAMI studies and GUSTO influenced so many of us who were in training during that era. Every AHA and ACC annual meeting was marked by Eric at the podium describing another important randomized trial that he had led, often with Rob Califf. So you can imagine my surprise. I skip most of these types of emails, but this title and its author compelled me to click through.

What I found was a 5-minute video of Topol making an argument that randomized trials are an anachronism and no longer fit what we need. He describes a trial using crenezumab, to prevent Alzheimer’s disease in high-risk individuals, that depends on surrogate endpoints. He says that these are the trials of the future — restricted to patients at risk and using surrogate markers. I cannot find this trial by searching for crenezumab on, but I assume from the press release Eric references that it is randomized.

Then he says what we need is surveillance of every patient in a trial — that we should have conditional approval of a new drug or device (without a trial?) and then monitor everyone treated. He goes on to decry the “contrived clinical trial environment” and says we “need to get to the real world.”

Because it is Eric Topol presenting this argument, this piece on Medscape is worth a viewing. It would be a big change to approve first and evaluate later — and to get rid of the randomized trial.

What’s your view of Topol’s proposal?

3 Responses to “Topol: The Clinical Trial World Is “Contrived””

  1. I am puzzled by Dr. Topol’s description of the Alzheimer’s trial

    “Researchers will be testing a drug that binds amyloid, a monoclonal antibody, in just [300][1] family members. They’re not following these patients out to the point of where they get dementia. Instead, they are using surrogate markers to see whether or not the process of developing Alzheimer’s can be blocked using this drug.”

    I could not find the trial on either, but I found a New York Times article and a Alzheimer Research Forum article describing the trial. According to ARF,

    “Importantly, the trial is intended not as an exploratory study, but as a registration trial, meaning a positive outcome might form the basis for a new drug application, said Reiman. Toward this end, primary outcome measures will be a composite cognitive battery and other cognitive tools. Various brain imaging tests, including amyloid PET and fluid biomarkers, will be secondary outcomes.”

    So the primary outcome measures are based on cognitive tests — not surrogates. The secondary endpoints are surrogate endpoints.

    With respect to the elegant matching of the biological defect and the specific drug intervention, my comment would be that the road to hell is paved with biological plausibility (apologies to Steve Nissen).

  2. Robin Motz, M.D., Ph.D. says:

    Surrogate endpoints assume an unproven cause-and-effect relationship between biological markers and clinical disease. Just look at the many arguments and studies of CRP or CA-125. I don’t think that pulling down on the arrow indicator in the lobby of an office building lowers the elevator.

  3. Leon Hyman, Ms M.D. says:

    I find it hard to believe that Dr. Topol wanted to eliminate Randomized trials which include is the drug reasonably safe. Even after a randomized trial it takes 10 years or more to fully appreciate the hidden side effects of a drug. The cardiovascular risks although small of the macriolide antibiotics just recently were revealed. His idea would take us back to 1937 when 100 children died from poisoning from a sulfalinamide antifreeze mix.