Decades ago, drugmakers in the United States could sell medicines without demonstrating that they actually worked.
That came to an end in the early 1960s after tens of thousands of women worldwide gave birth to children with severe birth defects after taking the inadequately tested drug thalidomide. Few of these tragedies occurred in the United States, thanks to the work of Dr. Frances Kelsey, an astute Food and Drug Administration scientist who kept the drug off the American market. The thalidomide debacle persuaded Congress to pass a law in 1962 requiring companies to test their drugs extensively before they could be sold.
Since then, American patients and doctors could assume that the medications we take or prescribe have been found to be sufficiently safe and effective by the F.D.A. That careful review process set the standard for drug evaluation worldwide.
But the strength of that process has been eroded, and it reached a low point last week when the F.D.A. approved aducanumab, a treatment for Alzheimer’s disease that has not been convincingly shown to work and can cause brain swelling and hemorrhage.
In recent years, under steady pressure from the pharmaceutical industry and the patient groups it funds, the F.D.A. has progressively lowered its standards of effectiveness and safety required for drug approvals. New drugs are now more likely to be supported by fewer studies and less adequate clinical trial designs than in the past. Worse, about two-thirds of new drugs are now approved based on what’s called “surrogate endpoints” — changes in the body measured by lab tests that suggest a potential benefit — rather than whether a drug meaningfully affects how a person feels, functions or survives.
For aducanumab, the evidence that its manufacturer, Biogen, submitted to the F.D.A. showed no convincing effect on patients’ cognitive decline. Its two main trials were stopped early in 2019 because the company concluded its drug did not work. But the company later reanalyzed its data and concluded that some patients in one arm of one of the trials seemed to benefit from the drug, even though the other trials did not show any improvement.
The F.D.A. worked closely with the company to study the data. But after careful review, an outside advisory committee for the agency was nearly unanimous in its ruling that the drug had failed to show strong evidence that it worked. Committee members were also concerned about the drug’s safety, since about a third of patients taking a higher dose had evidence of brain swelling. One of us, Dr. Kesselheim, was a member of that committee and has resigned as a result of the F.D.A.’s inexcusable decision to approve the drug anyway.
In approving aducanumab, the F.D.A. shifted the goal posts. It unexpectedly approved the drug based on a theory that it could affect amyloid protein levels in the brain. Amyloid buildup in the brain is considered a marker for Alzheimer’s disease, but lowering amyloid levels with a drug has never been shown to slow cognitive decline. Dozens of investigational drugs have lowered amyloid levels without affecting the progression of this terrible disease.
Even worse, although aducanumab was tested only in patients with mild disease, the F.D.A. inexplicably approved it for use in any person with Alzheimer’s, regardless of severity. It enters the market now as a monthly intravenous infusion with a $56,000 price tag and the need for regular M.R.I. scans to monitor for the possible brain swelling it can cause.
The F.D.A. does require follow-up research for drugs approved based on such unsubstantiated measures, but the agency gave Biogen a full nine years to complete another trial. Millions of patients will have been treated and billions of dollars passed along to Biogen before we know whether it really works. Now that the bar has been lowered, other companies are likely to seek similar pathways to approval.
The aducanumab decision is the worst example yet of the F.D.A.’s movement away from its high standards. As physicians, we know well that Alzheimer’s disease is a terrible condition. But approving a drug that hardly works and causes such worrisome side effects is not the solution.
If pressure from drugmakers and their lobbyists compels F.D.A. administrators to continue to loosen their standards, we need a new organization to review drug approvals and make evidence-based assessments of their clinical impact, as other countries do. These assessments can help guide patients to decide whether they want to spend their money on these drugs, help physicians understand whether to prescribe them and help insurers determine whether to cover them.
The need for outside oversight is clear, given the continuing failure of the F.D.A. to listen to its advisers, stand up to industry and consumer-group pressure and draw clear distinctions between drugs that work and drugs that only cause changes in lab tests of uncertain relevance. We cannot let this regulatory erosion send us back to a pre-thalidomide era.
Aaron S. Kesselheim and Jerry Avorn are internists and professors of medicine at Harvard Medical School, where they direct the Program on Regulation, Therapeutics and Law at Brigham and Women’s Hospital. Dr. Kesselheim served on the F.D.A. advisory committee that reviewed aducanumab from 2015 until he resigned this month.
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Home » Analysis & Comment » Opinion | The F.D.A. Has Reached a New Low
Opinion | The F.D.A. Has Reached a New Low
Decades ago, drugmakers in the United States could sell medicines without demonstrating that they actually worked.
That came to an end in the early 1960s after tens of thousands of women worldwide gave birth to children with severe birth defects after taking the inadequately tested drug thalidomide. Few of these tragedies occurred in the United States, thanks to the work of Dr. Frances Kelsey, an astute Food and Drug Administration scientist who kept the drug off the American market. The thalidomide debacle persuaded Congress to pass a law in 1962 requiring companies to test their drugs extensively before they could be sold.
Since then, American patients and doctors could assume that the medications we take or prescribe have been found to be sufficiently safe and effective by the F.D.A. That careful review process set the standard for drug evaluation worldwide.
But the strength of that process has been eroded, and it reached a low point last week when the F.D.A. approved aducanumab, a treatment for Alzheimer’s disease that has not been convincingly shown to work and can cause brain swelling and hemorrhage.
In recent years, under steady pressure from the pharmaceutical industry and the patient groups it funds, the F.D.A. has progressively lowered its standards of effectiveness and safety required for drug approvals. New drugs are now more likely to be supported by fewer studies and less adequate clinical trial designs than in the past. Worse, about two-thirds of new drugs are now approved based on what’s called “surrogate endpoints” — changes in the body measured by lab tests that suggest a potential benefit — rather than whether a drug meaningfully affects how a person feels, functions or survives.
For aducanumab, the evidence that its manufacturer, Biogen, submitted to the F.D.A. showed no convincing effect on patients’ cognitive decline. Its two main trials were stopped early in 2019 because the company concluded its drug did not work. But the company later reanalyzed its data and concluded that some patients in one arm of one of the trials seemed to benefit from the drug, even though the other trials did not show any improvement.
The F.D.A. worked closely with the company to study the data. But after careful review, an outside advisory committee for the agency was nearly unanimous in its ruling that the drug had failed to show strong evidence that it worked. Committee members were also concerned about the drug’s safety, since about a third of patients taking a higher dose had evidence of brain swelling. One of us, Dr. Kesselheim, was a member of that committee and has resigned as a result of the F.D.A.’s inexcusable decision to approve the drug anyway.
In approving aducanumab, the F.D.A. shifted the goal posts. It unexpectedly approved the drug based on a theory that it could affect amyloid protein levels in the brain. Amyloid buildup in the brain is considered a marker for Alzheimer’s disease, but lowering amyloid levels with a drug has never been shown to slow cognitive decline. Dozens of investigational drugs have lowered amyloid levels without affecting the progression of this terrible disease.
Even worse, although aducanumab was tested only in patients with mild disease, the F.D.A. inexplicably approved it for use in any person with Alzheimer’s, regardless of severity. It enters the market now as a monthly intravenous infusion with a $56,000 price tag and the need for regular M.R.I. scans to monitor for the possible brain swelling it can cause.
The F.D.A. does require follow-up research for drugs approved based on such unsubstantiated measures, but the agency gave Biogen a full nine years to complete another trial. Millions of patients will have been treated and billions of dollars passed along to Biogen before we know whether it really works. Now that the bar has been lowered, other companies are likely to seek similar pathways to approval.
The aducanumab decision is the worst example yet of the F.D.A.’s movement away from its high standards. As physicians, we know well that Alzheimer’s disease is a terrible condition. But approving a drug that hardly works and causes such worrisome side effects is not the solution.
If pressure from drugmakers and their lobbyists compels F.D.A. administrators to continue to loosen their standards, we need a new organization to review drug approvals and make evidence-based assessments of their clinical impact, as other countries do. These assessments can help guide patients to decide whether they want to spend their money on these drugs, help physicians understand whether to prescribe them and help insurers determine whether to cover them.
The need for outside oversight is clear, given the continuing failure of the F.D.A. to listen to its advisers, stand up to industry and consumer-group pressure and draw clear distinctions between drugs that work and drugs that only cause changes in lab tests of uncertain relevance. We cannot let this regulatory erosion send us back to a pre-thalidomide era.
Aaron S. Kesselheim and Jerry Avorn are internists and professors of medicine at Harvard Medical School, where they direct the Program on Regulation, Therapeutics and Law at Brigham and Women’s Hospital. Dr. Kesselheim served on the F.D.A. advisory committee that reviewed aducanumab from 2015 until he resigned this month.
The Times is committed to publishing a diversity of letters to the editor. We’d like to hear what you think about this or any of our articles. Here are some tips. And here’s our email: [email protected].
Follow The New York Times Opinion section on Facebook, Twitter (@NYTopinion) and Instagram.
Source: Read Full Article