Several weeks ago, a U.S. Food and Drug Administration (FDA) advisory committee unanimously concluded that phenylephrine, an ingredient found in popular nasal decongestants sold under such brand names as Sudafed PE and Dayquil, works no better than a placebo in treating cold and allergy symptoms. And Yale School of Medicine researchers suggest there are other similarly ineffective drugs on the market.
Many patients may be using medications despite insufficient evidence about efficacy or safety. Some drugs made it to the market under a grandfather clause in 1962, when the FDA established new effectiveness requirements. Others were rushed through the FDA’s Accelerated Approval Program, an expedited approval process designed to more quickly get drugs to patients with serious diseases. Doctors also prescribe many drugs off-label. So, while a drug may be approved for one purpose, it can also be commonly used to treat conditions for which it was not evaluated.
But even in the most rigorous of clinical trials demonstrating efficacy, the strict participation requirements for trial volunteers often don’t match how the majority of patients will be taking the drug post-approval. “We have this problem where we haven’t had a high enough bar to evaluate drug efficacy and inform people who are making choices about this,” says Harlan Krumholz, MD, Harold H. Hines, Jr. Professor of Medicine (Cardiology). “There are a lot of drugs on the market with relatively little evidence, where it’s unclear whether they work, how much benefit they provide, for whom, and under what circumstances,”
How was the decongestant phenylephrine initially FDA-approved?
Phenylephrine, the drug in common decongestants, was approved by the FDA for over-the-counter use in 1976. At the time, the FDA had determined that the drug was safe, and studies suggested its effectiveness against congestion. The drug is sold in several forms, including oral pills and nasal sprays. In 2006, it became the main ingredient in OTC decongestants after an FDA law required an older ingredient, pseudoephedrine, to be moved behind counters because it could be illegally processed into methamphetamine. Fast forward to 2023. Researchers have conducted many more studies on the drug that have shown overwhelmingly that the oral formulation is clinically ineffective in reducing symptoms of congestion. The resulting advisory committee decision does not apply to nasal sprays, which are still thought to be effective.
So how did phenylephrine reach the market in the first place? One reason is that at the time of its approval, the FDA had used an endpoint it thought to be clinically meaningful. Prior studies had measured airflow and air pressure in the nasal passage to indirectly evaluate congestion. But now, the FDA considers clinical symptom scores, in which patients answer a questionnaire on nasal symptom severity, to be the gold standard for evaluating efficacy. On that scale, phenylephrine is not effective.
Furthermore, most of the original studies evaluated the drug in the context of the common cold, a highly variable illness. The FDA now acknowledges that measuring allergic rhinitis, in which patients experience more long-term congestion, would have produced more reliable results.
Finally, six of the seven studies considered in the 1970s were submitted by Sterling-Winthrop, one of phenylephrine’s manufacturers, which may have played a role in influencing the original panel’s decision.
Ineffective drugs on the market, it turns out, are not an anomaly. A notable example is oseltamivir [Tamiflu], a prescription anti-viral approved in 1999 for seasonal flu, based on its ability to increase the level of an individual’s antibodies. However, in 2014, researchers from the Cochrane Collaboration, a global not-for-profit that conducts systematic reviews recognized as the gold standard in analyzing aggregated health care data, raised doubts about the drug’s evidence, which was largely compiled under the sponsorship of the drug’s manufacturer, Roche. “When a rigorous review had been undertaken about those trials, they were found to have some marked limitations and left a lot of holes in the evidence,” says Krumholz. The consequences of this were costly—the U.S. government had spent over $1.5 billion stockpiling the drug in the event of a flu pandemic.
Accelerated approval pathway approves drugs with limited evidence
There are numerous examples of the FDA approving drugs when there are still questions of efficacy, says Reshma Ramachandran, MD, assistant professor of medicine (general medicine). The class of drugs where this most often happens, she explains, are those that go through the FDA’s Accelerated Approval Program. To reduce time, this process relies on markers known as surrogate endpoints, such as laboratory measurements or radiographic images, that researchers believe may be reasonable predictors of clinical benefit. These markers significantly shorten the time it takes for a drug to get approved, but do not directly measure clinical benefit.
This expedited pathway is intended for drugs designed to treat serious conditions such as cancers or neurodegenerative disease. “In oncology care, the FDA standard for approval is often less rigorous in terms of the amount of evidence that’s required because they’re trying to get products to market more quickly since the disease is so serious,” says Joseph Ross, MD, professor of medicine (general medicine) and of public health (health policy and management). “But what you end up with are fairly small trials testing drugs focused on endpoints, such as whether a tumor shrinks, as opposed to whether the patient actually feels better or lives longer.”
After they are approved, the FDA requires confirmatory trials that prove clinical benefit. And if these trials find the drug to be ineffective, they are supposed to be withdrawn from the market. However, too often, says Ramachandran, this does not happen.
Sometimes this is because there is no other drug available. “There’s a concern that clinicians won’t have anything to give to these patients,” Ramachandran explains. But even in instances of what Ramachandran calls “a slam dunk,” where confirmatory trials irrefutably find no benefit, the FDA has historically had a difficult time removing the drugs from the market. Up until last year, its process for drug withdrawal was long and arduous (recently passed legislation streamlines this process). And drug manufacturers frequently refused to withdraw the drugs voluntarily.
“We’re approving drugs much more quickly than we have in the past, with this idea that after approval, further studies can be done by the manufacturer to prove that the drugs are actually safe and effective,” says Ramachandran. “But this leads to a lot of problems because there’s no incentive for the manufacturer to do the studies—because they want to keep selling their drug.”
For example, the withdrawal process for hydroxyprogesterone caproate (Makena), a drug to prevent pre-term birth, lasted more than a decade. Although multiple confirmatory trials proved that the drug didn’t work, its manufacturers did not volunteer to withdraw it from the market. Bevacizumab (Avastin), a drug used to treat various types of cancers, was controversially approved for the treatment of breast cancer in 2008 based on surrogate endpoints—in this instance, tumor growth rate. But the trials didn’t prove whether the drug helped patients live longer or have increased quality of life. Once again, when further research found it ineffective against breast cancer, its manufacturer refused to remove it, says Ramachandran. As a result, these ineffective drugs remained on the market for years as the FDA undertook its own lengthy withdrawal process. It is still FDA-approved to treat colorectal, lung, kidney, and other kinds of cancers.
More recently, in June 2021, a drug for Alzheimer’s disease, aducanumab, received accelerated approval. The clinical trials found that the drug worked no better than a placebo and had significant side effects, including brain hemorrhages and swelling. But the FDA still approved the drug based on a surrogate endpoint, the amount of beta amyloid in the brain. This refers to protein plaques that researchers believe may be associated with Alzheimer’s disease. Indeed, dozens of studies have shown that this is a reasonable proxy measure, but doubts remain. “We’re still debating whether any of these Alzheimer’s drugs work, and they have substantial potential side effects,” says Krumholz. “Yet, there are these advertisements on TV that portray them as miracle drugs for restoring cognitive issues.”
The risk of off-label drug use
Furthermore, many drugs are approved for one narrow purpose but also are commonly used off-label. Gabapentin (Neurontin), and its cousin pregabalin (Lyrica), for instance, became FDA-approved in 1993 as anticonvulsants. But today, doctors prescribe it for “almost everything,” says Krumholz, including acute and chronic pain, mood disorders, and withdrawal symptoms, despite insufficient data. And the drugs are not without risks. In 2019, the FDA issued a warning that these drugs can lead to serious breathing difficulties in some patients.
“When doctors are frustrated and don’t know what to do, they often prescribe gabapentin. It’s a multi-billion-dollar drug,” he says. “But there needs to be much more evidence about where, when, and for whom these drugs are safe and effective.”
Clinical trials may not accurately reflect real world
Researchers design clinical trials to demonstrate the effects of drugs under well-controlled circumstances. Participants are enrolled into trials only after careful consideration of the trial’s eligibility requirements. As a result, elderly people, children, or those with serious medical diseases are often excluded due to their increased vulnerability. Historically, trials have also underrepresented women, as well as racial and ethnic minorities. “But in the real world, things are messy—patients are taking nine or 10 different medications, they’re older, they are more likely to have other medical problems that could make the drug work less well,” says Ross. “Things don’t play out the way they play out in the controlled environment of a clinical trial.”
“We’re not getting additional studies that actually ensure drugs are safe in patients that look like ours,” adds Ramachandran. “In reality, patients who have serious conditions are usually on a slew of other medications and have other conditions that they’re also dealing with.” By not requiring additional studies, she says, the FDA is shifting the burden of uncertainty on patients, who then must make decisions on whether to take a drug without sufficient evidence on how it may interact with any co-morbidities.
Ramachandran and her colleagues are working actively to shift this burden of uncertainty. She and Ross direct the Yale Collaboration for Regulatory Rigor, Integrity, and Transparency (CRRIT), which is dedicated to studying the efficacy and safety of available drugs. Ross is also a leader of the Yale University-Mayo Clinic Center of Excellence in Regulatory Science and Innovation (CERSI), a joint collaboration in which researchers work directly with the FDA in using large databases to better understand how an authorized drug or medical device works in the real world.
Addressing this issue will also require the realignment of FDA incentives. “Right now, a lot of incentives are toward speeding approval and ensuring patients faster access,” says Ramachandran. “But the FDA also needs to provide more steps in terms of making sure evidence is collected within a certain time period demonstrating that it’s safe and effective in patients like ours.” A 2023 article in JAMA Health Forum, co-authored by Ramachandran and Ross, recommends increasing the FDA’s post-market requirements for manufacturers, including requiring post-market efficacy studies and implementing expedited drug withdrawal.
Ramachandran says she is encouraged by the FDA’s advisory panel on phenylephrine. “It’s great that the FDA had an advisory committee meeting and presented the evidence that has been collected over the years—that many of us in primary care were well aware of—and is now hopefully going to make a decision to remove it from the market, at least in the over-the-counter setting,” she says. “We hope that for other new drugs coming to the market, where there are a lot more questions, that the FDA takes the same approach.”