NOTno matter the conflicts, there are drugs to be approved.
In a sad turn of events, the Food and Drug Administration faces a grueling confidence debacle over its controversial approval of an expensive Alzheimer’s drug for which the evidence appears suspect at best.
Approval standards are called into question, and the acting FDA commissioner has asked a federal watchdog to investigate its relationship with Biogen, as the company has quietly worked to win favor with a senior official at the FDA instructed to review his drug.
This is far from being the definition of transparency.
This episode only renews concerns about the relationship between an agency tasked with reviewing drugs – and protecting public health – and the companies seeking to cash in on these drugs and having to pay the FDA high fees in the process. framework of the agreement.
And now another prominent FDA official is making the perception problem worse.
In remarks at an industry event last month, Patrizia Cavazzoni, a former Pfizer executive who heads the division that reviews drugs, complained about advisory committees charged with reviewing drugs. These are external expert groups, although the FDA is not obligated to accept their recommendations.
Specifically, she got annoyed at the conflict of interest rules that govern who the FDA can exploit for its committees.
“We have very strict conflict of interest rules that limit the pool of advisory committee members to a point, you know, in frustration, at least for me, where we have advisory committees that don’t seem to have any. experts in the field, “she said.” This is something… we are reflecting on “as part of a larger review underway in her division,” she said, adding that “last point but no least of all, we have to partner with the industry on this.
On the one hand, it is not at all clear that the lack of qualified experts is as big a problem as it claims. And second, it was a difficult time to raise the issue.
Let me explain.
Two decades ago, the FDA faced complaints about the financial ties between panelists and companies. So the agency wrote guidelines and then released a set of rules in 2008. Despite this, the FDA has always made exceptions through a waiver process for certain scenarios, such as when a sufficient number of experts are lacking.
Yet the pharmaceutical industry has regularly complained that the rules too often prohibit the best experts from joining a committee. In 2011, Margaret Hamburg, who was then FDA Commissioner, filed the same complaint.
Meanwhile, the number of exemptions was small. “I think the concerns about finding non-conflicting experts are a red herring. They have shown that they can find experts, which is illustrated by the low number of waivers, ”says Michael Carome of Public Citizen, the advocacy group.
Cavazzoni, however, also said that “the waiver process is not necessarily the way to solve” the problem, but she did not explain why.
So what do we know about the extent of the problem as Cavazzoni sees it? Not a lot.
I have asked the FDA for data on the lack of qualified experts and why the waiver process is insufficient.
Unfortunately my questions were not answered. Instead, a spokesperson wrote, “We continually review our advisory committee processes to ensure that they are effective and that they are in place to provide the most comprehensive advice possible to the FDA. We look forward to hearing stakeholder feedback on these efforts and achieving greater consistency within these critical advisory forums. “
A paper posted on the MedRxiv preprint server, however, may offer some clues to FDA thinking.
The document interviewed more than 400 people, half of whom were committee members and half were dismissed as panelists. due to conflicts. The “dominant view” was that current conflict policy could lower the quality of experts by excluding qualified experts, and lower the overall quality of contributions to committees. Result: The FDA should review its conflict policies.
But it smells a little sour, considering that half of those people have been left out due to conflict.
In any event, the authors, one of whom is an FDA official, proposed removing the general exclusion of universities that receive industry grants; exempt mutual funds and certain institutional investments, such as pension funds, held by panelists; and increase the current annual threshold of $ 50,000 for individual holdings in a business.
To a degree, I can understand some of the concerns.
There are shades of gray to consider, according to Genevieve Kanter, assistant professor of medicine at the University of Pennsylvania. In one study in 2014, she found a strong association between the biased voting of committee members who also served on company boards, but not those who receive research payments. “We need to be more nuanced about how we define financial conflicts of interest,” she told me.
Another possibility is that the current policy may result in more vacancies on committees. The percentage of open slots, in fact, has been creepy – hitting 18% last March from 14% four years ago, though it’s also not clear why. In addition, science and medicine are always evolving and sometimes there may be a limited number of experts available for a given committee examining highly specialized topics.
“Can you find people without conflicts? The answer might depend on the therapeutic areas, ”Daniel Carpenter, a professor of government at Harvard University who studied the FDA, told me. “Having said that, that doesn’t necessarily mean that’s the case for everyone.”
The situation is made more complicated by the relationship between the FDA and the pharmaceutical industry. Drug makers must pay FDA fees annually to help cover the cost of the agency’s operations. In fiscal 2021, pharmaceutical companies will pay $ 4.6 million.
But it turns the industry into something of a customer of the FDA.
And that brings us back to the Biogen controversy.
The FDA is under increasing pressure not only to approve more drugs faster, but also to address unmet medical needs such as Alzheimer’s disease, which often at the top of the list. The drug Biogen, in fact, was the first approved treatment for the disease in nearly two decades.
But the advisory board made it difficult for the agency. Last November, the panel voted almost unanimously not to recommend the drug for approval, citing uncertainty about the trial’s data and the benefits to patients. But after the FDA gave its approval anyway, three panel members resigned and one criticized the agency in a statement. letter which was distributed to the media.
It happened just four days before Cavazzoni spoke at the industry rally. And she had this to say:
“I’m going to say something that may not be welcomed by everyone, but I will speak with a personal observation,” she said. “We need to think about how to get back to the basic rationale of advisory committees, which is really to listen to thoughtful comments from experts in response to thoughtful questions we ask them. And see how we can remove some of the emotions… nuances or overtones. “
To be fair, it wasn’t clear she was talking about the Biogen reunion. And conflicts between the experts on the committee were not a problem. But it was hard not to notice the timing.
And the untimely outcome of this committee meeting can only add momentum to the composition of the review committee. The drug makers are likely to be enthusiastic. Alkermes CEO Richard Pops, who moderated the session, readily approved his feeling. “We must help you on [conflicts] to reign. They are too restrictive, ”he told her. “We don’t have any experts there.”
Unfortunately, making concessions to the pharmaceutical industry by relaxing the rules has one notable downside – it could make dissent more likely to be curbed or eliminated, and could also belittle the quality of scientific dialogue. And that wouldn’t help anyone.
So what to do? Work harder to find committee members. Yes, it’s easier said than done. And yes, this suggestion may infuriate some people. But that’s better than lowering the standards. And right now, the FDA should be working to raise the standards.