Drugs that go through the FDA’s “breakthrough therapy” program are approved more quickly, but are they safe?

A CNN report last week detailed the deaths of more than 700 patients prescribed an antipsychotic therapy drug for Parkinson’s disease.

The Food and Drug Administration (FDA) continues to monitor the use of Nuplazid (pimavanserin). But at this point, federal regulators see no reason to change the existing warnings placed on the medication, reports the San Diego Tribune.

The drug, sold by Acadia Pharmaceuticals, was approved under the FDA’s Breakthrough Therapy designation, one of four review programs meant to speed up the approval of medications.

The CNN report, though, has raised questions about whether faster approval has come at the expense of patient safety.

According to CNN, more than 700 deaths in patients prescribed Nuplazid were reported between the drug’s release on the market in June 2016 and March 2017.

The data comes from a November analysis by the nonprofit Institute for Safe Medication Practices (ISMP) and the FDA’s Adverse Event Reporting System (FAERS).

Nuplazid was approved in April 2016 to treat hallucinations and delusions associated with Parkinson’s disease psychosis. FDA reports that up to half of the people in the United States with Parkinson’s disease experience this condition.

As a “breakthrough therapy” drug, Nuplazid had to show, using early clinical data, that it offered substantial improvements over existing treatments. It was approved based on a six-week study of about 200 patients.

In an email to the San Diego Tribune, the FDA acknowledged that it had been aware of the drug’s “complex safety profile” since its approval.

The safety concerns led to special “black box” warnings on the product labeling — including that “elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death.”

The ISMP analysis also showed 487 reports of hallucinations among people prescribed the drug. The nonprofit said this likely shows “that the drug was making some psychosis worse, or in other instances, it was not providing the expected benefit.”

The FDA tracks “adverse event reports” like this for all approved drugs. These reports include deaths, side effects, and other issues experienced by people taking a medication.

They can be submitted to the agency by consumers, caregivers, or medical professionals.

Although adverse event reports raise concerns about the safety of Nuplazid, they don’t definitively show that the drug is more dangerous than expected.

“We don’t know if the drug is causing those deaths at this point,” said Jonathan Darrow, SJD, JD, MBA, a researcher at Harvard Medical School and Brigham and Women’s Hospital in Massachusetts.

According to CNN, Acadia analyzed the adverse event reports and found a lower mortality rate for people taking Nuplazid, compared to the rate among Medicare patients with Parkinson’s disease psychosis.

The network also interviewed researchers who pointed out that determining the true risks of Nuplazid would require additional scientific studies. These are routinely done before non-expedited drugs are approved.

In order to speed up the approval of breakthrough therapy drugs, however, the FDA accepts a lower level of scientific evidence.

“The evidence base is weaker than it might be perceived to be. The common perception is that you need randomized-controlled trials in order to receive FDA approval, and that is often not the case for these breakthrough drugs,” Darrow told Healthline.

Breakthrough drugs are approved based on less scientific evidence than other drugs because they are intended for people with a “serious condition,” according to the FDA.

But the preliminary clinical evidence should still show a “clear advantage over available therapy.”

Nuplazid was approved through the breakthrough therapy program because there was no other approved treatment for Parkinson’s disease psychosis.

Darrow, though, pointed out that another drug, clozapine, had been shown in an earlier randomized clinical trial to be effective as a treatment for this condition.

But the drug had never received FDA approval for use in Parkinson’s disease psychosis, which allowed Nuplazid to qualify for a breakthrough drug under the “no available therapy” standard.

According to the Friends of Cancer Research, the FDA, as of last month, had approved 87 breakthrough therapies. As hoped, these drugs reached the market faster.

In a study published this month in the New England Journal of Medicine, Darrow and his colleagues found that breakthrough drugs are approved on average three years faster than drugs that follow the usual FDA approval process — 4.8 years versus 8 years.

But drugs that are approved more quickly may also have more safety problems.

A study last year in JAMA found that drugs that received expedited approval were more likely to have a “safety event” after hitting the market. These issues include being withdrawn, having a warning added to the product labeling, or other safety communications.

This study did not include breakthrough therapy drugs because researchers looked at data from before that program was created by Congress.

Safety, though, is just one aspect of the equation.

“The greater concern with Nuplazid, from my perspective, is that it might not help patients much or at all,” said Darrow. “If there are unknown risks, why would you assume those risks if the benefit may be very near to zero.”

This is not an isolated problem.

In many cases, “breakthrough” drugs may not offer the large improvements that people expect when they hear that term.

In another study published in 2018 in the New England Journal of Medicine, Darrow and his colleagues found that among 16 breakthrough cancer drugs, 13 were completely effective in only 8 percent of patients; and 7 of the drugs were completely effective in less than 3 percent of patients.

Darrow said that “it’s not just a matter of the size [of the benefits], it’s also a matter of the certainty.”

Breakthrough drugs are approved using early clinical data, which may not always accurately assess the benefits. Larger studies done after approval may show that the drugs don’t work as well as expected.

People taking breakthrough drugs, though, often have few other options for treatment. And if their condition is serious — such as having terminal cancer — they may be willing to take a chance on a drug that has been approved more quickly but with less extensive testing.

Without having a clear sense of the real benefits, though, it’s difficult for patients and doctors to make an informed decision.

“My concern is that many physicians and patients will assume that if a drug is FDA-approved, it must be worth prescribing,” said Darrow. “That may not always be the case, based on a patient’s particular risk-aversion or risk-preference.”