Controversy erupted after the FDA’s 2021 approval of the Alzheimer’s disease drug aducanumab over an almost unanimously negative advisory committee vote.1 Although this might not sound ethical, “the agency listens to the outside advisors most of the time, and sometimes they don’t,” according to Peter Lurie, MD, MPH, president and executive director of the Center for Science in the Public Interest.
The FDA approves dozens of novel drugs each year. Not all those drugs go before an advisory committee. “There is a reflexive belief, among some, to just take everything before an advisory committee. But that’s not necessarily efficient or useful,” Lurie argues.
Drugs with clear evidence indicating whether there should be approval do not typically go before the advisory committee. “It’s the drugs that are tougher calls that do [go before an advisory committee], or if it’s the first drug in a certain class of drugs,” Lurie says.
During the opioid prescribing crisis, there was some debate over whether every new opioid should go before an FDA advisory committee. “Since scientists know a lot about opioids — what makes them safe and what makes them effective — to bring each and every one, with some only a minor variant on the previous one, to an advisory committee would not have been a good use of time. In the end, it didn’t happen,” Lurie says.
Some drugs are turned down initially for FDA approval based on the advisory committee’s negative vote, but receive agency approval eventually. It is possible the agency later obtained additional data that justified approval. If that additional data were brought to the advisory committee, members might have voted for approval.
Regardless, when there is a vacuum devoid of information, that leaves the public to use their imagination to speculate. One group of researchers wanted to learn more.
C. Joseph Ross Daval and colleagues examined the frequency and outcomes of cases in which the FDA approved drugs over the objections of an advisory committee. They analyzed all FDA advisory committee referrals for new drugs that were approved between 2010 and 2021.2
There was a dramatic decline in advisory committee review of approved drugs, from 55% to 6% annually. In 2010, half of drugs approved by FDA were reviewed by an advisory committee first. “But by 2021, advisory review of approved drugs was pretty unusual,” reports Daval, a postdoctoral research fellow at the Program On Regulation, Therapeutics, and Law (PORTAL) at Brigham and Women’s Hospital and Harvard Medical School.
Of 482 new drugs and biologics, 114 underwent an advisory committee review before FDA approval. Drugs were FDA-approved despite receiving a negative vote from an advisory committee at a median of one drug per year. In six of those cases, advisory committees voted negatively due to safety and efficacy concerns. In three cases, the committee voted negatively due to lack of evidence for a surrogate measure leading to clinical benefit. “Advisory committees can support public trust in the FDA if they’re used consistently,” Daval asserts.
Open advisory committee meetings could allow the public to view how the FDA makes key decisions and demonstrate that the agency takes the advice of independent experts seriously. When the FDA approves a drug, the justification for the decision is made public. The agency does not provide information on drugs that are not approved, although some of those drugs do go on to be approved months or years later. “What we really want is detail on why, at that moment in time, the product is not approved,” Lurie says.
In Lurie’s view, during the COVID-19 pandemic, communication with the public regarding vaccines worked relatively well; however, information on therapeutics and diagnostic devices were more controversial and problematic. “The differences between the two had to do with transparency,” Lurie offers. “The vaccines were handled, especially early on, in a very transparent fashion.”
The FDA released guidance, convened an advisory committee — even before any vaccines were up for approval — convened advisory committees for each vaccine that came up for approval, and did the same, for a period, for every booster. “As many difficulties as we’ve had in getting people to take the vaccine, and especially the boosters, it would have been much worse if the agency had not been as open as it was,” Lurie says.
This spotlights the importance of transparency in the FDA drug approval process. “In the modern environment, there’s a group of people who seem to believe that if they can’t see it, some kind of malfeasance must be lurking therein. Some of that can be allayed by transparency,” Lurie suggests.
It does not help matters that the FDA drug approval process, in general, is “quite opaque,” according to Lurie. “The truth is that it’s not actually public information unless the company chooses to make it so — until the drug gets approved or goes to advisory committee,” he says.
When a pharmaceutical company files a new drug application, that information is not publicly available until there is a decision to approve the drug, unless the company chooses to disclose it. If there is a decision not to approve the drug, that is not publicly available, either. If the company does not disclose it, the FDA’s reasons for why the drug was turned down are not made public.
“You don’t know that the application has been filed. You don’t know that the drug has been turned down. You may eventually learn that the product has been approved. But, except for that, technically the public is in the dark,” Lurie laments.
The notable exception is if the drug goes to an advisory committee. Convening the meeting implies the company has applied for drug approval. That also gives the public the opportunity to give input. “Because of a lawsuit that Public Citizen filed years ago, the briefing materials that are provided to the advisory committee members are also made public 48 hours before the meeting,” notes Lurie, adding that this offers an initial look at how the agency is viewing the drug.
“For all those reasons, the advisory committee is really an important part of the process,” Lurie concludes. “You can’t do it every time. But when it happens, it’s a unique moment in the drug approval process.”
“Our findings, especially the decrease in meetings for approved drugs, suggest that FDA may not be using advisory committees in a way that’s best for patients or providers,” Daval offers.
Daval says it would be prudent to create transparent criteria for how the FDA chooses to convene advisory committees, with the expectation that for certain types of decisions (e.g., accelerated approvals), the agency will consistently seek external advice before acting.
In response to this reporting, the FDA offered the following statement via a spokesperson: “At the FDA’s discretion, the agency may convene an advisory committee meeting on matters of importance to review issues and provide advice and recommendations. The FDA does not always convene an advisory committee meeting in connection with application reviews, but may do so when questions related to safety or the data submitted to support approval arise. These meetings can occur during any stage of a medical product’s review process, as well as after a product has been approved and marketed. The decision to involve an advisory committee is usually at the discretion of the review division.”
REFERENCES
1. Karlawish J, Grill JD. The approval of Aduhelm risks eroding public trust in Alzheimer research and the FDA. Nat Rev Neurol 2021;17:523-524.
2. Daval CJR, Sarpatwari A, Kesselheim AS. Unwanted advice? Frequency, characteristics, and outcomes of negative advisory committee votes for FDA-approved drugs. Health Aff (Millwood) 2022;41:713-721.
The FDA does not always convene an advisory committee meeting in connection with application reviews, but may do so when questions related to safety or the data submitted to support approval arise. In the modern environment, some believe if they cannot see it, foul play must be afoot. Some of that could be allayed by transparency and more public education.
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