(CNN) — Two years ago, Brendan Tyne pleaded with the Food and Drug Administration to approve a drug that he was hopeful could finally bring his mother some peace.

She could no longer move without assistance and had fallen victim to the debilitating and frightening psychosis that haunts many people with Parkinson’s disease.

“She thinks there are people in the house and animals are trying to get her,” he told an FDA advisory committee.

He believed that a new medication called Nuplazid, made by San Diego-based Acadia Pharmaceuticals, was the answer.

Nuplazid’s review was being expedited because it had been designated a “breakthrough therapy” — meaning that it demonstrated “substantial improvement” in patients with serious or life-threatening diseases compared to treatments already on the market. Congress created this designation in 2012 in an effort to speed up the FDA’s approval process, which has long been criticized for being too slow. Around 200 drugs have been granted this designation since its creation.

Still, to recommend approval, the advisory committee would have to find that the drug’s potential benefits outweighed its risks for its intended patients.

Some FDA officials concluded that Nuplazid’s public health benefit was enough to merit approval of the drug. Their argument echoed the pleas of family members and caregivers like Tyne: It could possibly help patients with no other alternative. Several of the people who spoke said their loved ones had been transformed during the clinical trials, though some said there was no way for them to know whether they were on Nuplazid or a placebo.

But the physician who led the FDA’s medical review, Dr. Paul Andreason, warned that patients taking the drug during the company’s clinical trials experienced serious outcomes, including death, at more than double the rate of those taking the placebo. The company’s limited testing, he said, had not convinced him that the benefits outweighed the risks.

While Tyne had heard about these risks, he said he “discounted death as a real statistical possibility” and was willing to try anything to help his mother.

“I have two young children who love their grandmother,” he told the committee. “If nothing is done to bring her back to some semblance of normalcy, my children will never remember their grandmother for who she is: a loving, funny, caring woman who has improved the lives of all of the loved ones who surround her. Please, I beg you, do not deprive my children and their grandmother of experiencing that love.”

‘You have to take it seriously’

The committee voted 12-2 and recommended that the FDA approve Nuplazid for the treatment of Parkinson’s disease psychosis based on a six-week study of about 200 patients. Three previous studies of the drug did not show that it was effective, Andreason said in his medical review, though they showed similar risk.

Even some committee members who voted in favor of the drug expressed reservations, according to the hearing transcript. “I guess I’m hoping that the risks are going to be small, and I think the benefits for some of these people who are very sick and whose families are affected by this, I think they’re probably willing to take that risk,” one physician stated. Another committee member said she wouldn’t have voted for the drug’s approval if there had been a safe and effective alternative on the market. A third made a “plea” to the FDA to “consider a large observational study so we can ensure that, once it goes into real-world use, that the benefits will outweigh the risks.”

It hit the market in June 2016. As caregivers and family members rushed to get their loved ones on it, sales climbed to roughly $125 million in 2017.

Tyne got his mother on the drug as soon as it became available. But after trying it for months, he says he was devastated to see that it was doing nothing to halt the awful progression of the disease, and her hallucinations became more frequent and harder to manage. “She has gone straight downhill to the point she really can’t function at all,” he said.

Shortly after the drug’s release, patients’ family members, doctors and other health care professionals started reporting “adverse events” possibly linked to the medication — including deaths, life-threatening incidents, falls, insomnia, nausea and fatigue. In more than 1,000 reports, patients continued to experience hallucinations while on Nuplazid.

In November, an analysis released by a nonprofit health care organization, the Institute for Safe Medication Practices, warned that 244 deaths had been reported to the FDA between the drug’s launch and March 2017. The organization also noted that hundreds of reports suggested the drug was “not providing the expected benefit” or potentially worsening the condition.

Tracked by the FDA, these so-called “adverse event reports” document deaths, side effects and other issues, and can be made directly by consumers, caregivers and other medical professionals. Reports are submitted to either the FDA or to the drugmaker, which is required to pass along any it receives to the federal government. In some cases, the person filing the report is convinced the side effects were caused by the drug; in others, the reporter ascribes no cause but notes that the patient was on the drug.

An adverse event report does not mean that a suspected medication has been ruled the cause of harm and is typically not the result of an official investigation. But the FDA uses the information to monitor potential issues with a drug and can take action as needed — updating a medication’s label, for instance, or restricting its use or pulling it off the market.

After analyzing the adverse event data for Nuplazid, the Institute for Safe Medication Practices concluded that this batch of reports “reinforces the concerns of those who warned that (Nuplazid) might do more harm than good.” Thomas Moore, senior scientist for drug safety and policy for the nonprofit, said the deaths are an “important warning signal” and warrant further review by the FDA — and possible action, depending on what the review finds.

Since the institute released its analysis, FDA data shows that the number of reported deaths has risen to more than 700. As of last June, Nuplazid was the only medication listed as “suspect” in at least 500 of the death reports.

Physicians, medical researchers and other experts told CNN that they worried that the drug had been approved too quickly, based on too little evidence that it was safe or effective. And given these mounting reports of deaths, they say that more needs to be done to assess Nuplazid’s true risks.

“This is almost unheard of, to have this many deaths reported,” said Diana Zuckerman, founder and president of the nonprofit thinktank the National Center for Health Research, adding that because reports are voluntary, potential problems may be underreported. “You just don’t see this with most new drugs — you don’t see all these reports — so you have to take it seriously.”

Acadia and the FDA maintain that the medication’s potential benefits continue to outweigh the risks and help fill a desperate need. Psychosis affects up to 50% of the roughly one million Americans suffering from Parkinson’s disease, according to the FDA, and Nuplazid is the first drug to be approved to treat this specific condition.

Acadia said there are a number of reasons for the higher volume of death reports. Parkinson’s disease psychosis is more commonly seen in patients in the most advanced stages of the disease, meaning they are already at a high risk of death. Plus, the company distributes Nuplazid through a network of specialty pharmacies that allow them to be in more frequent contact with both patients and caregivers — meaning it is more likely to receive reports of death, which it is required to pass along to the FDA.

“If you are actively and regularly engaging patients and/or caregivers, it is inevitable that you will see a higher number of adverse events reported, especially in an older, chronically ill patient population,” the company said in a statement.

Read Acadia’s full response here

It said its “benefit/risk assessment of Nuplazid remains unchanged,” and it carefully monitors and regularly analyzes safety reports from both ongoing studies and adverse event reports. The company noted, for example, that since the drug’s approval, two studies of a total of more than 300 patients with Alzheimer’s disease did not find a difference in the number of deaths reported between Nuplazid and the placebo.

The company also provided CNN with a statement from Dr. Joseph Jankovic, professor of neurology and an expert on movement disorders at Baylor College of Medicine. “I have accumulated a great deal of experience with this drug,” Jankovic said in the statement. “While not all patients are completely satisfied, many of my patients have experienced marked improvement in their visual hallucinations, paranoia and other psychotic symptoms.”

In an interview this week, FDA commissioner Scott Gottlieb was asked by CNN’s Dr. Sanjay Gupta about his thoughts on drugs that receive expedited reviews and then prompt concerns about safety once they become available, like Nuplazid. While Gottlieb didn’t want to comment on a specific product, he said he is “familiar with the circumstances” and that it’s very important for the agency to make sure it is “appropriately balancing” safety with medical need. He said this is a flexible standard, however, and there may be more tolerance for risk in situations where there is a significant need and patients don’t have an alternative.

“You’ve seen us take regulatory action recently in the post-market setting to limit the use of drugs when new safety concerns became known,” he said.

The FDA told CNN it will continue to monitor the adverse event reports and review the drug’s safety. It added that Nuplazid’s “complex safety profile,” recognized at the time of its approval, resulted in a requirement that the medication carry a number of warnings on its label so that doctors could analyze potential risks and benefits before prescribing the drug.

The cases reported so far, according to the FDA, typically involved elderly patients with advanced-stage Parkinson’s disease who suffer from numerous medical conditions and often take other medications that can increase the risk of death.

“Based on these data, the FDA has, at this time, not identified a specific safety issue that is not already adequately described in the product labeling,” the agency said in a statement.

The FDA has required antipsychotics to carry its most severe “black box” warning for the treatment of elderly dementia patients, after studies found that the medications increase the risk of death in this population. Between 50% and 80% of Parkinson’s patients experience dementia as the disease worsens, according to the Alzheimer’s Association. Because Nuplazid is a new kind of antipsychotic that targets a different receptor in the brain, its maker claims it comes with fewer toxic side effects. Even so, Nuplazid also carries a black box warning.

Related: The little red pill being pushed on the elderly

Geriatric psychiatrist and former FDA medical officer Susan Molchan said that the number of deaths is alarming and questioned whether patients and their families are aware of the risks associated with the drug.

To determine the true risks of Nuplazid, the researchers interviewed by CNN said, the FDA needs to require further scientific studies — and not just rely on the reports, which are challenging to interpret and are not systematically collected. They also worried that, because the drug was already approved, these studies and any action by the FDA could take years.

Hundreds of adverse event reports

A CNN review of several hundred adverse event reports shows that the detail provided for each case varies widely and that thorough investigations are rarely conducted — making it difficult to determine whether Nuplazid might have been involved in the deaths of already sick and elderly patients.

In these reports, the physicians who prescribed the drug sometimes suggest that their patients likely died from complications from Parkinson’s rather than because of Nuplazid. In other cases, it’s unclear when exactly the patient started or stopped taking the medication. And in yet others, family members and sometimes doctors are convinced the drug contributed to the deaths.

One report recounts the death of a 73-year-old woman in a long-term care facility who was taking Nuplazid. Just before 8 in the morning, a nurse noted that the woman was “sleepy.” Shortly after, she was found unresponsive and without a pulse. Paramedics were not able to revive her and, less than an hour after the nurse’s visit, she was pronounced dead. While her physician didn’t believe her death was “related” to Nuplazid, her husband was convinced that it had played a role and paid for an autopsy. It showed only that she had pre-existing heart issues and died of cardiac arrest.

Related: Sick, dying and raped in America’s nursing homes

In another report, an 89-year-old man was taken off the drug after experiencing a significant decline. His doctor blamed Nuplazid for his deteriorating condition. The patient died weeks later. In a third report, a woman flagged her husband’s death to the FDA after he was taken to the hospital due to dehydration. After he passed away, she said, she was told by “someone at the hospital” that the death was connected to his use of Nuplazid.

Acadia said it analyzed these reports and concluded that there “is nothing to suggest a causal relationship to Nuplazid.” Acadia calculated a mortality rate for Nuplazid, which it said was lower than what you’d see in the general population of Parkinson’s disease psychosis patients covered by Medicare. It calculated this using deaths reported to the FDA and what it considered a conservative estimate of patients on the drug, along with Medicare claims data. However, multiple experts interviewed by CNN said that this is an unreliable calculation since it is comparing apples to oranges.

Widening the patient pool

In the weeks after the Institute for Safe Medication Practices issued its report on the deaths, Acadia’s stock price dropped by more than 20%. While many large investors remain bullish about the stock, some investment analysts have made public records requests to the FDA for the death reports.

Currently, Nuplazid can cost nearly $100 a day, according to wholesale pricing data from First Databank. That can add up to more than $30,000 a year for a single patient, though the amount a patient actually pays depends on factors including individual insurance coverage.

Acadia expects sales of Nuplazid to at least double this year.

The company, meanwhile, is forging ahead with clinical trials in an attempt to get the medication approved for use in a larger patient population: patients who have dementia-related psychosis. In October, the FDA granted its coveted breakthrough designation for this potential use as well, meaning it will also undergo a speedier review process.

While a doctor can legally prescribe a drug for any reason, insurance companies may not approve it for uses that are not FDA-approved. So FDA approval to treat dementia patients would likely result in Nuplazid being prescribed to a much wider population, concerned medical experts told CNN.

“You would certainly hope they don’t approve it for anything else,” said Zuckerman of the National Center for Health Research, based on the current research and FDA adverse event reports. “If they’re going to approve it for another group of patients that is much, much larger — that would be unconscionable.

“That is something they should absolutely not do given these unanswered questions about risk.”

‘I wouldn’t have gotten my hopes up’

Roughly two years have passed since that FDA meeting, where family members and caregivers — some of whom traveled there on Acadia’s dime — gathered with medical experts to debate the merits and potential risks of Nuplazid.

Andreason, the physician who led the FDA’s medical review of Nuplazid, no longer works for the agency.

He said that while he stands by the warnings he made at the time, he understands that other antipsychotics used to treat Parkinson’s patients also come with an increased risk of death and that, when patients have a debilitating disease like Parkinson’s, physicians and caregivers may choose a medication that improves quality of life even if it could also shorten life expectancy.

He said that he was not surprised to hear about the reports of death.

“This is exactly what I thought was going to happen,” he said. “We were going to get a burst of reports of serious adverse events and deaths.”

Dr. Stephanie Fox-Rawlings, a senior fellow at the National Center for Health Research who spoke against the drug’s approval at the FDA committee meeting, recently told CNN she understands how desperate families in these situations are, but she does not think Nuplazid is the answer based on her review of Acadia’s public research. She and Zuckerman said that, after previous studies didn’t show it was effective, the drugmaker changed the way the medication’s ability to improve psychosis was measured, which resulted in a positive outcome. Acadia said its studies have had different objectives and all of them have used “consistent, appropriate, and validated assessment methodology.”

“If patients know there is some level of benefit, they can judge their risk,” said Fox-Rawlings. “But if we don’t even know that it does work, how do you even judge that? It’s kind of a false hope.”

Kim Witczak was the consumer representative on the FDA committee evaluating Nuplazid. She and the patient representative were the only two members to vote against its approval. She still can’t believe it’s on the market.

“I remember leaving really, really frustrated,” she said.

CNN reached two of the three family members who petitioned for Nuplazid’s approval at the meeting, despite having had no experience with the drug or its clinical trials, to ask whether they tried the medication once it hit the market.

One of these was Elaine Casavant. Despite the “staggering cost” of the medication, she said, she was quick to get her husband on it. But after three months, he showed no improvement and they stopped the medication. She has heard success stories, however, and remains optimistic that the drug could be helping certain people.

The other person was Tyne.

The 43-year-old New Jersey resident works in New York and visits his mother every weekend at a nursing home in the Bronx. Tyne has attempted to move on from the disappointment of Nuplazid, but he still gets frustrated talking about it.

“Knowing what I know now — that it didn’t work at all — I wouldn’t have gotten my hopes up,” he said.

But he doesn’t regret trying.

“If there was something that could possibly help my mom and I didn’t do it, I wouldn’t be able to look at myself in the mirror.”

Source: http://sacramento.cbslocal.com/2018/04/09/fda-risk-drug-deaths/