Los Angeles – Federal regulators are increasingly approving drugs before studies have shown they work, leaving patients at risk of taking prescriptions that might harm but not help them.
Last year, 14 new drugs received so-called expedited approval, in which they did not undergo the testing that the Food and Drug Administration routinely requires. This represented 28% of the 50 drugs approved by the FDA. The numbers jumped from 2018, when just four, or 7%, of 59 new drugs were approved under these rules.
The rules were created to be used in rare cases where critically ill patients had no other treatments. But with pressure from the pharmaceutical industry, patient groups and politicians to get drugs to market faster, most drugs are now approved under fast-track approval rules or through three similar programs requiring less evidence and regulatory control.
The change has alarmed some experts who fear the industry is exploiting the rules to sell drugs of questionable efficacy and safety at exorbitant prices.
“It’s causing tremendous real damage,” said Jerome Hoffman, professor emeritus of medicine at UCLA, pointing to side effects and medical bills that patients simply cannot afford.
Although the FDA has the authority to withdraw these drugs when studies later show the drugs don’t work, this decision has been rare.
A recent Los Angeles Times investigation detailed how Covis Pharma refused the agency’s request to withdraw a drug for pregnant women at risk of preterm birth. The FDA approved the drug called Makena a decade ago in hopes it would reduce death and severe disability in infants born too early. The FDA asked the company to perform a study to prove the drug’s benefits. That lawsuit lasted eight years and “failed to unequivocally demonstrate” that Makena worked, agency scientists said.
Dozens of drugs currently on the market have not yet been backed by studies confirming their effectiveness.
There is no requirement to inform patients that they have been prescribed any of these drugs – a shortcoming that has some doctors worried people are being misled.
“I think people generally assume that when the FDA has approved something, there’s overwhelming evidence that it’s safe and effective,” said Joseph Ross, professor of medicine and public health at Yale, who wrote on how the rules should be reformed.
In a statement, the agency said it was “committed to ensuring the integrity of the Accelerated Approval Program.”
“We believe that patients who currently lack adequate treatment options for serious or life-threatening illnesses are willing to accept some uncertainty regarding clinical benefits when a new therapy is developed,” the FDA said.
“In the vast majority of fast-track approvals,” he said, the clinical benefits of the drug were then verified through the required confirmatory studies.
For decades, the standard for FDA approval was two “adequate and well-controlled” studies showing “substantial evidence of efficacy.”
In 1992, with the crisis of the AIDS epidemic, the agency launched its accelerated accreditation program. The program allows companies to use so-called “surrogate endpoints” – certain signs in clinical trials that show a drug might benefit patients.
Many of the drugs approved under the program are cancer drugs that have not been shown in trials to prolong life. Instead, the companies used X-rays and other measurements to show that the drug seemed to elicit a positive response.
Since 1992, Congress has passed laws adding more ways for drugs to get faster approval with less evidence than the FDA has long required.
The new programs were introduced to help patients with rare diseases and without further hope. Now they are commonly used.
Last year, 74% of the 50 new drugs approved by the FDA’s Center for Drug Evaluation and Research received some form of accelerated approval. Among the drugs on this list are those for heart failure and lupus, conditions for which patients already have several drugs available.
“Forget two studies, forget well-done studies, forget randomized trials,” Hoffman said of the FDA’s growing use of expedited approvals. “It’s now if someone says it might work and we haven’t yet proven it’s harmful – let’s try it.”
If a company gets fast-track approval, the FDA requires studies to confirm the drug works. But the agency has often failed to compel companies to complete these studies, which could halt sales if they fail.
“Companies are dragging their feet,” Ross said. “Studies are not done.”
Asked about the delayed trials, an agency spokesperson said, “The FDA will use all authorities at its disposal to encourage the diligent initiation of well-designed confirmatory studies. If there are gaps in the FDA’s ability to hold developers accountable to conduct studies as quickly as science allows, the agency will work with Congress to close those gaps.
In an increasing number of cases, companies continue to sell the drugs even after these studies have been completed and shown that the drugs are not effective. Ross and other researchers call these “pending approvals.”
“Makena is illustrative of this whole dance that’s going on,” Ross said.
Covis told the FDA that it wanted to continue selling Makena while it did more research to try again to show its effectiveness. The company disputes the results of the study that didn’t show it worked, saying it didn’t include enough black women, who are at the highest risk of preterm birth. Covis says the drug is safe and continued prescriptions will not harm pregnant women. Makena’s label lists side effects such as blood clots and high blood pressure. Some doctors worry about the risk of stillbirth. The evidence will be considered at a hearing the FDA has yet to schedule, even though it’s been three years since the trial showed Makena didn’t work.
Two recent accelerated approvals have raised more questions about whether the FDA has lowered the bar too much.
Last year, the agency sparked controversy when it overturned the decision of its panel of outside experts and granted approval for a drug called Aduhelm for Alzheimer’s disease, which affects 6 million Americans and is incurable. Three committee members resigned in protest.
In the decision, the FDA used evidence from clinical trials that showed the drug reduced levels of amyloid plaque in the brain. But scientists have questioned the use of this surrogate marker, pointing out that other drugs have targeted the plaques with little effect on a patient’s dementia.
Infusions of the drug can cause serious side effects, including brain swelling.
Biogen, the maker of the drug, introduced Aduhelm at a price of $56,000 per year. The high price of the drug for a disease that affects millions of Americans prompted federal officials to propose a 14.5% increase in Medicare premiums to cover the billions of dollars the government expected to pay for it. In December, the company halved the annual price to $28,200.
In January, Medicare offered to cover the cost of Aduhelm only for patients in clinical trials. A final decision is pending.
Further concerns about the fast-track approval program were raised in 2016 when Janet Woodcock, a senior FDA official, approved a drug for Duchenne muscular dystrophy despite agency scientists’ findings that it would not. did not work and its risks were not yet known.
Sarepta Therapeutics began selling the drug Exondys 51 for $300,000 a year. The approval sparked a dispute within the FDA that quickly became public when the documents were released.
“By allowing an ineffective drug, essentially a scientifically elegant placebo, to market, thousands of patients and their families would be given false hope in exchange for hardship and risk,” wrote Ellis Unger, one of the FDA scientists. who denounced Woodcock’s decision.
Woodcock defended his shot. Among her arguments was that Sarepta “needed to be capitalized”, she told an internal committee set up to review the dispute. She pointed out that the company’s shares fell when a panel of experts voted against the drug, then rose when she later sent a letter to Sarepta saying she expected to grant approval soon. drug accelerated.
She wrote that if the drug is not approved, Sarepta would have insufficient funding to continue studying Exondys 51 and other similar drugs in its pipeline.
The agency’s spokesperson told The Times that “FDA’s decision on any drug product, in any disease area, is based on an evaluation to determine whether the drug’s benefits outweigh its risks. This assessment is informed by science, medicine, politics and judgment, in accordance with applicable legal and regulatory standards.
Patients depend on doctors to protect them from drugs that have more risks than benefits. Yet a report suggests most doctors are unaware of the scant evidence behind some of the drugs they prescribe.
In a 2016 survey, 70% of physicians mistakenly believed that FDA approval required studies showing both a “statistically significant” and “clinically important” effect.
“The pharmaceutical company and all the publicity is saying this is a great new drug,” Hoffman said. “How many doctors are actually going to go up and say, ‘Wait a second. Is it really true?
Expensive drugs whose effectiveness has not yet been proven
The FDA approves more drugs before studies show they work. Although their effectiveness has not been proven, some come to market with high list prices.
Exondys 51: Duchenne muscular dystrophy, $300,000 per year
Aduhelm: Alzheimer’s disease, $28,200 per year
Makena: Premature birth, $13,000 per pregnancy