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Timely treatment decisions: the promise of surrogate markers

Layla Parast, PhD
Meds
January 4, 2023
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Driving around, searching for children’s Tylenol and a pharmacy that had the antibiotics my son needed, was not how I wanted to spend the holidays. I am not alone – shelves are bare, and antibiotics are in short supply as we head into the new year in the midst of a triple threat of COVID-19, flu, and RSV.

While this drug shortage is incredibly frustrating, at least there is treatment. For many diseases, there is no treatment, and there is no cure.

Clinical studies to evaluate new treatments and preventative interventions often require years of follow-up. Recently released results from the Women’s Health Initiative, two randomized clinical trials conducted among over 27,000 women evaluating the effect of hormone therapy on breast cancer incidence, were based on 20 years of follow-up.

A unique exception was the remarkably fast development, testing, and production of COVID-19 vaccines, which was unprecedented and driven by overwhelming pressure from patients and policymakers worldwide.

Long follow-up for clinical trials is necessary to ensure that treatments are both safe and effective. But delaying treatment for patients in need can be deadly.

The pressure to develop and demand a timely COVID-19 vaccine highlights both the power and lack of patience among patients and policymakers. The public was not willing to wait 20 years for a COVID-19 vaccine, and they are not willing to wait 20 years for treatment for Alzheimer’s disease or any other debilitating chronic disease either. Nor should they have to wait so long.

Surrogate markers may be the answer. A surrogate marker is a biomarker or outcome that can be used to replace the primary outcome in a clinical study and can be observed earlier. For example, instead of waiting 20 years to observe breast cancer incidence, an alternative may be to examine changes in gene expression profiles after two years.

A valid surrogate marker has the potential to allow researchers to make quicker decisions about treatments and get effective treatments to patients sooner.

There have been many successes with surrogate markers. A blood test now checks for abnormal proteins called amyloid beta and may indicate whether one has or will develop Alzheimer’s disease.

Images from positron emission tomography (PET) scans can provide early evidence of cognitive decline. Numerous drugs have been approved by the Food and Drug Administration (FDA) based on evidence from surrogate markers, allowing these drugs to be made available sooner to patients in need.

Vaccines, in particular, are commonly evaluated and approved based on the surrogate of immune system response rather than disease incidence itself.

To be sure, there have also been several failures with surrogate markers. The most dramatic example of this was seen in clinical trials for treatments for ventricular arrhythmia, as described in the 1995 book, Deadly Medicine: Why Tens of Thousands of Heart Patients Died in America’s Worst Drug Disaster, by Thomas J. Moore.

Ventricular arrhythmia is strongly associated with death and was generally accepted as a surrogate for death. Several drugs were shown to lower the incidence of ventricular arrhythmia and were approved by the FDA. Unfortunately, these drugs actually increased the risk of death.

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Clinicians, statisticians, and epidemiologists are actively working on the complex open problems related to surrogate markers, including how to validate a surrogate and identify when a surrogate is valid for one study but not another.

I lead a $1.3 million study, funded by the National Institutes of Health, to identify surrogate markers in diabetes and examine heterogeneity in the utility of a surrogate, an especially important and timely issue.

This occurs when a surrogate marker is useful for only certain subgroups of the population – perhaps only women, only older individuals, individuals with no family history of chronic disease, or individuals in certain racial/ethnic groups.

Surprisingly, even if clinical experts, patients, and the FDA agree on a surrogate marker and a treatment demonstrates effectiveness based on the surrogate marker, this does not mean that patients can get the treatment sooner.

Because ultimately, doctors do not decide what treatments patients receive. Payers do.

The drug aducanumab received accelerated approval by the FDA as a treatment for Alzheimer’s disease based on its ability to decrease beta-amyloid plaques, a surrogate marker for Alzheimer’s disease.

However, the Centers for Medicaid & Medicaid Services (CMS), the payer for health care for the vast majority of patients with Alzheimer’s disease, does not cover the drug unless the patient is taking the drug as part of a clinical trial. At a launch price of $56,000 per year, lack of coverage effectively limits access for patients.

CMS’s decision in April 2022, which has received both scathing criticism and strong support, was based on study results ultimately failing to show any effect on cognitive outcomes.

This lack of coverage is not limited to Medicare, as Blue Cross Blue Shield similarly does not cover the drug.

Payers must not decide what treatments patients can receive. It is not unreasonable for patients to expect that if the FDA approves a drug, their insurance should cover it.

But with that expectation comes incredible responsibility on the shoulders of the FDA. There are numerous examples of the FDA approving a drug early based on the demonstrated effect on a surrogate marker and subsequent study results failing to demonstrate an effect on the primary clinical outcome.

To uphold confidence in the treatments approved by the FDA, they must have a comprehensive, timely, and transparent system to both approve drugs early based on surrogate markers and withdraw that approval in the future if there is evidence to support that.

The use of surrogate markers to make decisions about a treatment sooner can save lives. But it requires a compromise between waiting 20 years to approve a new treatment and rushing treatment decisions. It should be up to patients, clinicians, researchers, policymakers, and payers to work together to decide on the cost of that compromise effectively.

Layla Parast is a statistician.

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