Deficient drug approval

For decades, the U.S. Food and Drug Administration was respected around the world. That’s because it protected the American public from disastrous drug side effects. In addition, it set a high bar for drug approvals. Pharmaceutical manufacturers had to prove that their drugs actually helped patients more than they harmed them. 

A drug company that wanted the agency to approve its medicine needed to present significant data from two convincing clinical trials. These needed to show that the product was reliably better than an inert but indistinguishable placebo product.

A recent decision by the FDA has undermined its credibility. The agency approved aducanumab (Aduhelm) to treat Alzheimer disease not because it addresses the symptoms or slows a victim’s slide into stupor but because it reduces a marker in the brain. In fact, as the FDA itself explained, it used the accelerated approval pathway because that permits approval based on biochemical measurements instead of clinical improvement.  They call this a “surrogate endpoint.”

In this case, the marker is beta-amyloid, a tiny piece of a protein found in the brain. No one doubts that the brains of people with Alzheimer disease are full of plaques with bits of beta-amyloid stuck together. The hypothesis is that these plaques cause the disease. But this idea remains unproven and controversial.

Aduhelm does reduce beta-amyloid plaques in the brain. No one disputes that. The question is whether this will make an important difference for patients and their families.

This is not the first time the FDA has approved a drug based on a surrogate endpoint. Alirocumab (Praluent) and evolocumab (Repatha) are recent cholesterol-lowering medications. When added to statins, they dramatically reduce “bad” LDL cholesterol. FDA approved these medications based on cholesterol measurements.

The understanding was that the companies would conduct clinical trials to see if they also prevent heart attacks and death. In a recent review, these drugs lowered LDL cholesterol successfully, but the reduction in death from coronary heart disease was not statistically significant (Journal of Clinical Medicine, Apr. 5, 2021).

Changing a surrogate endpoint is not the same as offering clinical improvement. Dr. Matthew Schrag is a neurologist who does research at Vanderbilt University Medical Center. He offered this analogy in the Washington Post (July 16, 2021):

“Even if amyloid does cause Alzheimer’s disease, it does not necessarily mean you can cure the disease by removing it. If someone came to the emergency room with a stab wound, just removing the knife wouldn’t cure them either.”

FDA has also used accelerated approval for cancer drugs. A number of drugs have been approved based on their ability to shrink tumors. That seems like a good thing, but it doesn’t ensure a longer, healthier life.

A commentary in JAMA Internal Medicine (May 28, 2019) noted:

“Response rate is not itself a meaningful clinical outcome; the size of a tumor does not matter if patients’ lives are not extended or if their quality of life is not improved.”

And yet drug companies can take your money for lowering cholesterol, reducing blood sugar or removing beta-amyloid from your brain without demonstrating any clinical benefit. In other words, the outcomes you actually care about (a healthier, longer life) do not have to be established to achieve FDA approval.

A new study in JAMA says that faster FDA drug approvals may not be better.

Everyone wants the latest, greatest treatment for Alzheimer disease, diabetes, cancer or heart disease. However, we need to be cautious about embracing drugs approved on the basis of surrogate endpoints. These medications, which are frequently extremely expensive, don’t necessarily improve patients’ lives.