Never mind the conflicts, there are drugs to approve.
In a sorry turn of events, the Food and Drug Administration is facing a confidence-draining debacle thanks to its controversial approval of a pricey Alzheimer’s drug for which evidence appears suspect, at best.
Approval standards are being questioned and the acting FDA commissioner asked a federal watchdog to probe its dealings with Biogen, because the company quietly worked to curry favor with a top FDA official in charge of reviewing its drug.
This is hardly the definition of transparency.
This episode only renews concerns about the relationship between an agency that is chartered with reviewing medicines — and protecting public health — and companies that seek to profit from these drugs and must pay the FDA handsome fees as part of the bargain.
And now, another prominent FDA official is compounding the perception problem.
In remarks during an industry event last month, Patrizia Cavazzoni, a former Pfizer executive who heads the division that reviews medicines, complained about advisory committees tasked with assessing medicines. These are panels of outside experts, although the FDA is not obligated to accept their recommendations.
Specifically, she chafed at conflict of interest rules that govern who the FDA can tap for its committees.
“We have very stringent conflicts of interest rules that limit the pool of advisory committee members to a point, you know, of frustration, at least to me, where we have some advisory committees that don’t seem to have experts in the field,” she said. “That’s something… we’re giving some thought to” as part of a broader review underway at her division, she said, adding that “last but not least, we need to partner with industry on this.”
For one, it’s not at all clear that a lack of qualified experts is as big a problem as she claims. And second, this was a fraught moment to raise the issue.
Let me explain.
Two decades ago, the FDA faced complaints about financial ties between panelists and companies. So the agency drafted guidelines and later issued a set of rules in 2008. Even so, the FDA has made exceptions that have always been made through a waiver process for some scenarios, such as when a sufficient number of experts are lacking.
Yet the pharmaceutical industry has regularly complained that the rules too often preclude the best experts from joining a committee. In 2011, Margaret Hamburg, who was FDA commissioner at the time, made the same complaint.
Meanwhile, the number of waivers has been small. “I think concerns about finding experts who are not conflicted are a red herring. They’ve demonstrated they can find experts, which is illustrated by low numbers of waivers,” says Michael Carome of Public Citzen, the advocacy group.
Cavazzoni, however, also said “the waiver process is not necessarily the way to address” the issue, but she did not explain why.
So what do we know about the extent of the problem as Cavazzoni sees it? Not much.
I asked the FDA for data about a lack of qualified experts and why the waiver process is insufficient.
Unfortunately, my questions weren’t answered. Instead, a spokesperson wrote that “we continually review our advisory committee processes to make sure they are efficient and are set up to provide the most thorough advice to the FDA as possible. We look forward to hearing feedback from stakeholders on these efforts and to achieving greater consistency within these critical advisory forums.”
A paper posted on the MedRxiv preprint server, though, may offer some clues about the FDA’s thinking.
The paper surveyed more than 400 people, half of whom were committee members and half of whom had been rejected as panelists due to conflicts. The “prevailing opinion” was that the current conflicts policy could lower the quality of experts by excluding qualified experts, and lower the overall quality of input to the committees. The upshot: the FDA ought to review its conflicts policies.
But this smells a bit like sour grapes, given that half of those folks were excluded due to conflicts.
In any event, the authors, one of whom is an FDA official, proposed eliminating blanket exclusion of universities that benefit from industry grants; exempting mutual funds and certain institutional investments, such as pension funds, held by panelists; and increasing the current $50,000 annual threshold for individual holdings in a company.
Up to a point, I can understand some of the concerns.
There are shades of gray to consider, according to Genevieve Kanter, an assistant professor of medicine at the University of Pennsylvania. In a study in 2014, she found a strong association between biased voting by committee members who also served on company boards, but not those receiving research payments. “We do have to be more nuanced about how we define financial conflict of interest,” she told me.
Another possibility is the existing policy may cause more committee vacancies. The percentage of open slots, in fact, has been creeping up – hitting 18% this past March compared with 14% four years ago, although it’s not clear why, either. Moreover, science and medicine always evolve and, at times, there may well be a limited number of experts available for a given committee reviewing highly specialized topics.
“Can you find people without conflicts? The answer might depend on the therapeutic areas,” Daniel Carpenter, a Harvard University professor of government who has studied the FDA, told me. “That said, it doesn’t necessarily mean that’s the case with all of them.”
The situation is made more complicated by the relationship between the FDA and the pharmaceutical industry. Drug makers must pay the FDA fees each year to help cover the cost of agency operations. In fiscal year 2021, pharmaceutical companies will pay $1.1 billion.
But this transforms the industry into an FDA client of a sort.
And this brings us back to the Biogen controversy.
The FDA has been under increasing pressure to not only approve more drugs more quickly, but to respond to unmet medical needs such as Alzheimer’s, which often tops the list. The Biogen drug, in fact, was the first treatment approved for the disease in nearly two decades.
But the advisory committee made it difficult for the agency. Last November, the panel voted nearly unanimously not to recommend the drug for approval, citing uncertainty about the trial data and patient benefits. But after the FDA issued approval anyway, three panel members resigned and one slammed the agency in a letter that was distributed to the media.
This occurred just four days before Cavazzoni spoke to the industry gathering. And she had this to say:
“I’m going to say something that may not be welcomed by all, but I will speak with a personal observation,” she said. “We need to give some thought on how to get back to the fundamental reasons for advisory committees, which is really listening to thoughtful input from experts in response to thoughtful questions that we ask them. And see how we can remove some of the emotional… undertones or overtones.”
To be fair, it was not clear she was speaking about the Biogen meeting. And conflicts among committee experts were not an issue. But it was hard not to notice the timing.
And the inconvenient outcome of that committee meeting may only add impetus to further review committee membership. Drug makers are likely to be enthusiastic. Alkermes chief executive Richard Pops, who moderated the session, readily endorsed her sentiment. “We have to help you on the [conflicts] rule. They’re overly restrictive,” he told her. “We’re not getting experts there.”
Unfortunately, making concessions to the pharmaceutical industry by loosening the rules has a notable downside — it might make it more likely that dissent is curbed or eliminated, and could also cheapen 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 exasperate some people. But it’s better than lowering standards. And right now, the FDA should be all about raising standards.
This column was updated to note the amount of user fees to be paid by drug makers.