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00:53 - Source: CNN
CNN  — 

A drug safety watchdog has renewed its criticism of the government’s approval of a Parkinson’s psychosis medication and is calling for stronger warnings on its label for patients and their families.

Deemed a “breakthrough” medication, Nuplazid received an expedited review and was approved by the Food and Drug Administration in 2016. The agency ruled that the potential benefits for a desperate patient population outweighed its risks, making it the only drug on the market approved to combat hallucinations and delusions in Parkinson’s patients.

In the wake of a high number of death reports submitted to the federal government about patients taking Nuplazid, the FDA conducted a safety evaluation last year. It announced in September that it had found no “new or unexpected” risks that weren’t already taken into account at the time of approval and deemed no further action was necessary.

But a report released Wednesday by a team of medical researchers, safety experts and doctors at the nonprofit Institute for Safe Medication Practices, or ISMP, says that the underlying documents from the FDA’s evaluation leave a number of questions about the drug’s safety and efficacy unanswered. As a result, the institute said it does not believe the “reassurance” from the FDA was warranted.

Both the FDA and drugmaker Acadia Pharmaceuticals – which is under investigation by the Department of Justice for its sales and marketing of Nuplazid – have stood by the drug. They have attributed the number of deaths to an already sick population and the company’s distribution system. Acadia distributes Nuplazid through a network of specialty pharmacies that has made it more likely the company would learn of deaths from both patients and caregivers, which it is required to pass along to the FDA. The majority of the death reports reviewed by the FDA were submitted to the agency by Acadia. “If the reporting rate from the specialty pharmacy channel were as low as it was from other channels, the overall mortality reporting rate would be 88% lower,” an FDA official wrote in documents from the agency’s safety evaluation of Nuplazid last year.

The FDA declined to comment on the ISMP report, saying “in general the FDA does not comment on individual studies or reports, but evaluates them as part of the body of evidence to further our understanding about a particular issue and assist in our mission to protect the public health.”

Acadia disputed the findings of the ISMP report, calling them “severe mischaracterizations and conjecture about the safety and efficacy of NUPLAZID” and said the report did not provide a complete characterization of the “benefit/risk profile” of Nuplazid.

ISMP said it stood by its full report, saying it “is a scientific report that is based on published data, FDA documents, and experience of our expert project team. … The source documents and information we cite provide abundant support for our findings of fact and conclusions about drug risks and benefits.”

Before the FDA launched this most recent safety review, ISMP had issued a report in 2017 about the adverse events being reported to the FDA, noting that the agency’s medical reviewer had recommended against the drug’s approval in 2016.

Now, in the wake of the FDA’s September conclusion that no changes were needed and that Nuplazid’s current label adequately describes its risks, the group is again arguing that Nuplazid was approved by the federal government too quickly, without strong enough evidence that its benefits outweigh its risks.

“The FDA should re-evaluate whether this drug has benefits that outweigh its still poorly defined risks,” the report states. “We continue to agree with the original medical review of [Nuplazid] that recommended against approval.”

Related: New Parkinson’s psychosis drug target of DOJ investigation

In response to the ISMP report, Acadia cited the FDA’s conclusion, including how Nuplazid’s distribution system contributed to the high number of reports of death and other adverse events. The company told CNN it is committed to “rigorous and ongoing safety monitoring and reporting.”

Authors of the ISMP report noted that deaths of patients taking Nuplazid have continued to be reported to the FDA and urged the agency to modernize its reporting system so it is better able to identify whether deaths or adverse events are related to medications patients are taking. In the case of Nuplazid, ISMP said FDA safety reviewers had found that many of the death reports contained too little detail to determine whether Nuplazid had been a contributing factor – a problem ISMP said was not unique to Nuplazid.

The FDA determined that Nuplazid’s risks are already captured by the drug’s label, which includes a black box warning. But ISMP said it is worried that this warning – which cautions that there is an “increased mortality in elderly patients with dementia-related psychosis” – is not clear.

Nuplazid is only approved to treat Parkinson’s Disease Psychosis, or PDP, and is not approved to treat dementia. However, the FDA confirmed to CNN that this black box warning is intended to apply to PDP patients as well – meaning they are also at an increased risk of death.

When two Florida public defenders wrote to the Broward Sheriff’s Office last week that a mentally ill woman, Tammy Jackson, had been forced to give birth alone in her jail cell, they slammed the facility and its medical staff for putting both her and her infant daughter at “grave risk.”

It also recommended the label go further to explicitly warn doctors not to prescribe the drug in combination with other antipsychotics, which have been shown to double the risk of death in Parkinson’s patients.

Acadia pointed to an FDA statement in which the agency reminded doctors to be aware of the risks of using Nuplazid with other antipsychotics, saying in the same statement that it had noticed “potentially concerning prescribing patterns.” The company previously told CNN that patients, caregivers and prescribers need to consider Nuplazid’s label and black box warning in the context of each patient’s “assessed benefit/risk and other factors” – including their age and the severity of their condition.

Beyond the watchdog’s concerns about safety, ISMP said it remains unconvinced that Nuplazid is helping patients. It said the agency may have “erred” when it approved Nuplazid based on the efficacy found in one clinical trial – even though no “statistically significant benefit” had been shown in three earlier studies, as the FDA has noted in public documents. Acadia continues to tout the drug’s efficacy, noting that the successful six-week study of about 200 patients “demonstrated clinically robust and highly statistically significant efficacy,” and that the drug’s approval was based on this as well as “other supportive studies.”

Dr. Daniel Weintraub, an Acadia consultant and Parkinson’s disease expert, did not share the same level of concern about Nuplazid as the authors of the ISMP report, but suggested that more clinical testing and other research be conducted since there is “currently insufficient data … to state that Nuplazid is or is not associated with an increased mortality or morbidity risk in patients with Parkinson disease psychosis.” Weintraub, who CNN asked to review the ISMP report, also said that in his interpretation, the label states that the black box warning only applies to those with dementia-related psychosis. Therefore, a prescriber reading the label would likely deem that it applied to only those PDP patients who also suffer from dementia, he said.

CNN has heard from several family members who say the drug helped tame their loved ones’ hallucinations with few apparent side effects, and several prescribing physicians have said they don’t have any concerns about the drug and have welcomed an FDA-approved option for such a difficult condition. Other people have questioned whether Nuplazid contributed to their family member’s decline or death or said the drug didn’t work.

Company data cited in the FDA review showed that nearly half of patients taking the drug since it hit the market had died or discontinued Nuplazid, whether because of cost, efficacy, side effects or other reasons, within the first two months of taking the medication. Acadia said that there are a wide variety of reasons people discontinue a medication, including “those that are often unrelated to the drug.”

The company pointed to review documents from the FDA’s Division of Psychiatry Products, which said that “the reporting rate of deaths relative to the total number of patients taking [Nuplazid] changes little with length of exposure. If [Nuplazid] were causing a significant number of deaths, those deaths would be more likely to occur and to be reported within the first few weeks or months of use.”

The ISMP report said its concerns about the drug’s efficacy were “reinforced” by this company data – suggesting that the high discontinuation rate was from patients getting off the drug because it didn’t work, not necessarily due to death. And the FDA previously told CNN that “the most likely reason for stopping was that they didn’t find it to be helpful.”

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