What’s Wrong with the FDA?

If Robert Califf, the White House nominee for commissioner of the U.S. Food and Drug Administration, is confirmed by the Senate, he’ll take the reins of an agency with its reputation in tatters. Once revered as the global leader in drug regulation, the FDA has approved one bad drug and medical device after another over the past 30 years, leaving staff demoralized and overseas regulators scratching their heads. Meanwhile, about a third of Americans refuse to get vaccinated for COVID-19, in part because they distrust government and scientific institutions. 

In the case of the FDA, at least some of that mistrust is deserved even if the COVID vaccines are generally safe. (We’ve both taken them.) The most recent FDA disaster erupted in June, when officials approved the Alzheimer’s drug Aduhelm over the objections of the agency’s biostatistician and an 11-member committee of expert advisers. The data submitted by Biogen, the drug’s manufacturer, failed to show that Aduhelm is effective. It also poses a significant risk of harm, including brain bleeds and swelling in about a third of test subjects. Agency higher-ups decided to overlook these shortcomings and put the drug on a fast track for approval. 

Three members of the FDA advisory committee promptly quit in protest over the Aduhelm decision, and multiple hospital systems have refused to administer the wildly expensive drug, fearing it doesn’t work, will hurt patients, and will break their budgets. (The drug is priced at $28,000 a year per patient.) Thanks to its eye-popping price, the Centers for Medicare and Medicaid Services raised its premiums by 14.5 percent, the largest increase in its history, half of which was to accommodate this one drug. It’s no wonder that European regulators gave Aduhelm a thumbs-down, and Japan appears ready to follow suit. On January 11, the CMS announced its preliminary decision not to pay for Aduhelm except for patients enrolled in high-quality clinical trials, saying “important questions” remain about the drug. That decision should be finalized later this year. 

The Aduhelm debacle and other FDA blunders can be traced to declining scientific standards at the agency and increasingly cozy ties with the companies it regulates. Multiple FDA officials have passed through the revolving door from industry to government and back again, but not before leaving behind regulations and controversial approval decisions that benefited manufacturers. In a 2016 study, most officials who left the FDA after reviewing cancer drugs for the agency went to work for biotech companies. 

Aside from advancing their careers, FDA higher-ups have another powerful incentive to make decisions that serve corporations over patients: the agency’s heavy dependence on industry funding. In 2019, approximately 61 percent of the FDA’s $2.5 billion budget for drug approvals (including biotech drugs) came from user fees charged to manufacturers. Those fees are mandated by a 1992 law passed by Congress to speed up drug approvals. 

But speed can lead to disaster: The pain medicine Vioxx was fast-tracked for approval in 1999. By the time it had been pulled from the market four years later, it had killed an estimated 60,000 Americans. One-third of all new drugs approved since 2000 have turned out to have safety problems. Those approved through the fast-track process, or “accelerated approval pathway,” are even more likely to be withdrawn or slapped with mandatory warnings about serious complications, including death. “Our current system for testing drugs before they go on the market is very weak,” says Rita Redberg, a cardiologist at the University of California at San Francisco and editor in chief of the medical journal JAMA Internal Medicine. 

Patients and the public need radical reform at the FDA and a commissioner who will champion a return to sound science and loosening, if not cutting, the agency’s financial ties to the companies it is supposed to be regulating. 

Unfortunately, Robert Califf is probably not that commissioner. The 71-year-old cardiologist previously served as FDA commissioner under President Barack Obama from February 2016 to January 2017, after being passed over for the job in 2009 because he was widely seen as too close to the drug industry. Despite conflicts of interest that included financial relationships with 23 companies, Califf sailed through confirmation as FDA commissioner with only a handful of senators objecting to his industry ties. 

This time may be different. On January 14, Califf’s nomination was sent to the full Senate following a 13–8 vote in the Committee on Health, Education, Labor and Pensions. Democrat Maggie Hassan of New Hampshire and independent Bernie Sanders of Vermont voted against Califf, while four Republican members supported him. Three more Democratic senators have said they’ll vote against confirming Califf when it comes to the floor: Ed Markey of Massachusetts, Richard Blumenthal of Connecticut, and Joe Manchin of West Virginia. Each, like Hassan, has expressed concern about the FDA’s handling of the opioid crisis. Senate Democratic leaders will need at least five Republican votes, which would give Vice President Kamala Harris the tie-breaking vote to confirm the nominee. 

During his brief tenure as FDA commissioner in the Obama administration, Califf did little to slow the flood of useless or dangerous drugs. Notably, he supported the controversial decision to approve eteplirsen (brand name Exondys 51), a drug for the rare but fatal muscle-wasting disease Duchenne muscular dystrophy. Studies of eteplirsen have never shown that it slows, much less stops, the progression of the disease. Califf passed the buck and left the final decision to Janet Woodcock, then head of the FDA’s Center for Drug Evaluation and Research. Woodcock is currently acting FDA commissioner and has championed the drug internally. 

Califf has only grown closer to industry since the Obama years. According to disclosure documents filed in July 2020, his ties span more than two dozen drug and biotech companies. He was paid $2.7 million by Verily Life Sciences, the biomedical research organization operated by Alphabet Inc., and he has a massive stock portfolio with millions of dollars invested in biotech. This issue was taken up only briefly during his confirmation hearing in December. Pointing to the revolving door at the FDA, Senator Sanders said, “At a time when the American people pay the highest prices in the world for prescription drugs and as drug companies continue to be the most powerful special interest in Washington, we need leadership at the FDA that is finally willing to stand up to the greed and power of the pharmaceutical industry.” 

All of which suggests there’s not much chance that Califf would be the reformer the FDA needs. With eternal hope that the full Senate will reject him or, if he’s confirmed, he and the White House will pursue a reform agenda, we talked to several experts about their priorities for fixing the agency. In their view and ours, the following represent the top five actions that need to be taken. 

1. Enforce commitments made by drugmakers.

The FDA awards expedited or fast-track approvals for drugs with a promise by the manufacturer that it will conduct further, more rigorous studies. However, by 2018, according to a recent review, companies followed through on only 38 percent (166 of 437) of drugs. 

To ensure that studies get done, the agency must fully implement the National Academy of Medicine recommendations for a modern post-market tracking system. Such a database needs to log all studies of drugs on the market, published and unpublished, and all cases of harm, and it needs to be publicly available so outside researchers can keep watch on safety data and the FDA. The agency should also immediately withdraw drug approval when the manufacturer fails to conduct agreed-upon follow-up studies. 

2. Rescind the approval of drugs that cause harm but don’t benefit patients.

When follow-up studies show that drugs are ineffective or dangerous, the FDA needs to pull them. Right now, drugs are still being prescribed to patients even though rigorous clinical trials have shown they don’t work. The agency recently allowed four out of six widely used (and heavily advertised) cancer drugs to stay on the market after their follow-up studies failed to show any benefit. Only five of 54 costly, toxic cancer drugs approved by the agency between 2008 and 2012 improved survival rates.

The FDA should immediately rescind approval for eteplirsen, the drug for Duchenne muscular dystrophy. Ditto the Alzheimer’s drug Aduhelm, which sets a precedent at the FDA for multiple similar medications that are waiting in the wings. Those should be forced to go through a thorough scientific vetting process rather than being approved on the same lousy reasoning that led to Aduhelm’s release. 

3. Restore rigorous scientific standards.

Many experts, including multiple FDA insiders, have complained about the progressive decay of scientific standards at the agency. This has only gotten worse since 2016, with the passage of the 21st Century Cures Act, which gives the FDA enormous leeway in what kinds of studies it demands of companies in order to get their drugs approved. The FDA needs flexibility, says Steven Goodman, associate dean of clinical and translational research at Stanford, “but it has been erring on the side of lowering the scientific bar.”

For most drugs, companies should be required to produce two randomized clinical trials, the gold standard of medical science, showing that the drug provides meaningful benefit. Fewer drugs should be approved based on a “surrogate marker,” often an imaging study or blood test that is affected by a drug but may have little to do with whether or not patients benefit. “Too many FDA decisions have been based on wishful thinking rather than medical evidence,” says Diana Zuckerman, president of the National Center for Health Research, a Washington, D.C.–based public health think tank. 

4. Clean house.

Somebody needs to jam the revolving door at the FDA. Physicians, scientists, and administrators come to the agency from industry, push industry-friendly decisions, and then leave government for new, lucrative positions in the private sector. 

Take Patrizia Cavazzoni, the head of the FDA Center for Drug Evaluation and Research, who oversaw the approval of Aduhelm. Before joining the agency in 2019, Cavazzoni spent nearly two decades in high-level positions with the pharmaceutical giants Pfizer, Eli Lilly, and Sanofi-Aventis. After overruling the FDA advisory committee’s resounding vote against Aduhelm, she suggested that industry “partner” with the FDA in choosing committee members, an idea that violates the whole point of having outside, independent advisers. 

Next up for the exits should be agency officials who seem to have forgotten who they serve. Billy Dunn, head of the Office of Neuroscience, met privately with Biogen officials after the FDA advisory committee’s no vote on Aduhelm. He then lobbied others at the agency to approve the drug, calling the ridiculously shaky scientific evidence presented by the company “extremely persuasive.” 

Public Citizen, a nonprofit consumer advocacy group, has called for the removal of Cavazzoni and Dunn, along with FDA Acting Director Woodcock, who, despite having no financial ties to industry, has repeatedly supported agency decisions based on flimsy scientific evidence. 

5. Stop Big Pharma financing.

Finally, President Biden should call on Congress to fully fund the FDA by repealing the legislation mandating that the drug industry pay for its own reviews. “What really needs to happen is to mitigate the power that Pharma already has over the FDA,” says Erick Turner, professor of psychiatry at Oregon Health & Science University and a former member of an FDA advisory committee. That can’t happen as long as the FDA is dependent on industry money. 

Fully funding the FDA won’t be cheap. Still, other agencies that do a better job of regulating, like the Federal Aviation Administration and the Consumer Product Safety Commission, are supported by taxes. Surely the U.S., with the largest economy in the world, can afford the $2.5 billion annual cost of overseeing the approval of drugs without the help of industry largesse. 

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