Inside the Sausage Factory of Drug Approval: Nuplazid (pimavanserin) coverage didn’t inspect closely enough

The FDA’s drug approval process was in the news earlier this month when Nuplazid (pimavanserin), a new drug to treat the hallucinations and delusions that sometimes accompany Parkinson’s disease, was approved.  Anyone knowing anything about FDA drug approvals knows how hard it is to predict outcomes after a lengthy and complicated process comprised largely of experts closely scrutinizing the minutiae of drug research data, and discussing those data in multiple and lengthy advisory committee meetings. Easily this could be likened to the making of sausages, where a wide variety of ingredients must pass through messy and largely opaque machinery before emerging in the form of a big capsule.

sausage in factoryThe squeamish would do well not to look too closely

And yet journalists have an obligation to translate the finer details of the drug approval process for news consumers. Nuplazid approval stories in STATFOX NewsHealthDay, and Reuters hit many of the main points but varied in the amount of detail provided. Few, for example, explained what the drug’s “breakthrough” status meant — even though the newly created designation is the primary basis of the drug’s speedy approval. We’ve seen stories about other new drugs that also neglect to clarify what that means.

As the FDA notes, a drug can qualify as a breakthrough — meaning it is eligible for expedited review — if it is:

  • intended alone or in combination with one or more other drugs to treat a serious or life threatening disease or condition; and
  • preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development.

Approval based on a single small study

In this case, the “preliminary clinical evidence” supporting the drug’s approval consists of a single six-week study with 199 patients. Clearly this eyebrow-raising fact was glossed over by many news outlets (as well as by the company news release we reviewed by the drug’s manufacturer Acadia), and the stories left the breakthrough designation issue largely unchallenged. Some articles were thorough in summarizing the effects of the drug, but few questioned the clinical significance of a three-point change in a 9-point scale as reported in the Lancet. And there was little scrutiny of the fact that, compared with placebo, five times as many pimavanserin patients discontinued the drug during the trial because of adverse effects. The STAT story helpfully referred back to the FDA briefing documents, reminding us that for every two patients who are expected to achieve ‘much improved’ status as a result of Nuplazid, one patient experiences a serious adverse event.

A few stories, including a short one at FOX News included the important caveat that “Nuplazid will carry a boxed warning about the risks of death when used in older patients with dementia,” adding that “the drugs are not approved for that use.” HealthDay told us how small the one trial was and how much the drug is likely to cost: “expected to be priced at $13,500 per patient for a year.”  

There were, however, some unjustified (and unchallenged) statements in the reporting that might tend to paint the drug in too rosy a light. Marketwatch quoted Michael Okun, medical director of the National Parkinson Foundation, who said that the approval “represents a major paradigm shift in the treatment of Parkinson’s disease psychosis.” The only paradigm being shifted, in my opinion, is seeing a decisive 12-2 vote in favor of a drug that the FDA says must wear a black box warning, indicating it increases the risk of death in the demented elderly. Before quoting Okun’s cheerleading comments, MarketWatch would have done well to disclose that Okun’s foundation takes money from Acadia as well as several other drug companies.  

Patient advocate stresses potential for harm

One person who doesn’t share Okun’s enthusiasm is Kim Witczak, who knows a few things about the drug approval process and has attended many FDA advisory hearings over the years.  She was there as one of two consumer and patient representatives, watching as pimavanserin entered the sausage factory.

For her the key issue is the “breakthrough” designation, which the company achieved a few years ago and which allowed them to seek approval based on a single small study. She told me: “I was shocked about the lack of numbers in the clinical trial and what ‘breakthrough’ therapy designation really means.” In her opinion consumers and their doctors need to know a lot more about the drug approval process–and that the drug’s modest effects are counterbalanced by the potential for adverse effects. That’s why she voted against it, telling me: “For every two patients who had a 50% reduction in psychosis–a third has an adverse event.” 

Even though Nuplazid is required to carry the FDA-mandated Black Box warning that all the other antipsychotics are required to carry (warning of risk of death if used in the elderly with dementia), Witczak believes it will be used ‘off label’ for all kinds of things. She picked up that fact by listening closely to what the Wall Street analysts were saying about the drug, and listening in as the company’s CEO spoke to market analysts. She said: “Some analysts said the drug had a potential $2-$3 billion market ‘off-label’.” Which is to say the market could be massively expanded to millions of schizophrenics or patients with Alzheimer’s: Not bad for a drug that was taken for six weeks by 95 patients.

Shouldn’t physicians and consumers hear about the negative studies?

Journalists can learn a lot about drug approvals in the US, a process which starts with the FDA’s Center for Drug Evaluation and Research (CDER) and its team of “physicians, statisticians, chemists, pharmacologists, and other scientists.” Those experts review the presented data, and the proposed labeling to establish if a drug’s health benefits outweigh its potential harms. The FDA advisory committee process then exposes that evidence to hearings containing consumer, academic and industry experts, who can further interrogate the data, a process that is largely open to the public.

For Susan Molchan, a geriatric psychiatrist who is on the board of the National Physician’s Alliance and is an expert in dementia in the elderly, the reporting of this drug approval had a key fact omitted: the issue of publication bias.  That’s when studies, usually negative ones, don’t get published or publicized and so their results aren’t factored into the larger body of evidence on a drug. A drug company could conceivably conduct any number of studies to demonstrate the effect of their drugs, and eventually they’ll get one that looks good. In the case of this new drug to treat Parkinson’s there were at least two other failed studies, as indicated in the FDA documentation. The real bias, she says, is that “we’re only hearing about the positive one, and the negative ones are buried.”  She added, “This is a big flaw, and with the ‘breakthrough’ designation they only require minimal research, often just one clinical trial with few people on the drug.”  The bias induced by buried studies would suggest the drug is even less effective than it appears. 

Dr. Molchan often treats Parkinson’s patients with these types of symptoms and the first thing she tries to do is reduce the doses of the dopamine drugs like L-DOPA or Sinemet. She wondered how this new drug would fare against the existing comparators such as lower doses of dopamine drugs or the antipsychotic Seroquel which is often used in these patients.  

Physicians misunderstand what FDA approval really means

Long-time journalists who report on the FDA know it’s very hard for the agency to say “no” to approving a new drug, especially when there is no existing treatment for a particular disease. There is strong pressure to provide access to new medicines. However, FDA officials might be a bit more hesitant to green-light every breakthrough, game changer and paradigm shift that comes along if they knew how much their reports influenced consumers, and most importantly, physicians. According to this article in the Journal of the American Medical Association, (behind a paywall but reported here in Medscape) a sizeable majority (73%) “of the physicians incorrectly believed FDA approval meant the effectiveness of the drug was similar to the effectiveness of other approved drugs.”  And 70%” incorrectly believed both statistically significant and clinically significant effects were required for FDA approval.”

That misunderstanding has “consequences,” according to Drs. Lisa Schwartz and Steve Woloshin who designed this survey. They write that the fact physicians don’t understand the drug approval process “may lead physicians to overprescribe newly approved drugs—particularly breakthrough therapies—and inadequately communicate how well these drugs work to the patients who will use them.”  

And that’s something we should all feel a little squeamish about.​

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Mike Guiltinan

May 23, 2016 at 1:03 pm

Since Pimavanserin obtained significant P=.001 change in several endpoints and from 3 different raters the FDA allowed a single P3 trial. A long term safety extension trial where some patients were on the drug for as long as 9 yrs also made the FDA’s decision a no brainer for a disease without a drug. Witczak has attended a lot of ADCOMs and usually voices a negative opinion.

Greg Wierenga

May 25, 2016 at 9:13 am

The two failed studies used a measurement that included criteria not germane to PDP. Acadia worked with FDA to refine this.