Posted 29 January 2013
By Alexander Gaffney, RF News Editor
The US Food and Drug Administration (FDA) often courts controversy with its decisions to approve or deny new therapies. In the wake of some high-profile scandals in the past decade, the agency has made its regulatory processes more transparent by opening up its advisory committees to more public input and fewer potential conflicts of interest. But, until now, few have asked a simple question: Are those changes leading to improved regulatory outcomes?
A new book, Regulatory Breakdown: The Crisis of Confidence in US Regulation, seeks in part to answer this question. A research piece contained within the book and authored by Susan Moffit argues that the committees are having some-but not all-of the effects desired when reforms were implemented: more public input, more issues raised, and fewer postmarket regulations actions required of FDA.
Background: The Vioxx Scandal
As long as there have been regulators, it seems, there have been scandals. Many have focused public attention and ire on the lack of legal authority given to regulators, such as the ethylene glycol and thalidomide scandals of 1938 and 1962 that respectively led to FDA being given the authority to require drug products to be shown to be safe, effective and manufactured to quality standards before being allowed on the market.
But in the 2000s, a different kind of scandal enveloped FDA regulators. Vioxx (rofecoxib), a blockbuster arthritis painkiller drug marketed by Merck, was withdrawn from the market in 2004 after researchers found that the drug caused unacceptably high cardiovascular adverse events. Tens of millions of Americans had been prescribed Vioxx, and as many as 139,000 additional heart attacks were thought to have been caused by the drug's effects.
In the wake of public hearings, legislators and public health officials alike grappled with a complex question: What was to be done?
Legislators would eventually focus a significant amount of their attention on the role of FDA's advisory committees, of which one-the Arthritis Drugs Advisory Committee-had recommended Vioxx for approval on two separate occasions. A legislative review of that committee found that it had numerous members with potential conflicts of interests.
Subsequently, FDA retooled its advisory committees such that financial ties were required to be disclosed and the committees, which had formerly been less than fully transparency with their information, began to disclose the majority of information available to regulators.
Are More Transparent Advisory Committees Better for FDA?
Now, several years after those reforms came into effect, Moffit wanted to probe the data to answer a question: "To what extent can a lack of policymaking transparency be linked with evidence of impaired product quality and regulatory failure?"
The theory behind Moffit's question is relatively straightforward. If advisory committees are less beholden to conflicts of interest, they can comfortably raise more issues, thereby allowing for a more frank discussion of those issues. More public participation, including better information afforded to them, will allow for the same. If advisory committee members are seen as having fewer conflicts of interest-even perceived ones-then their decisions will carry more weight with regulators, prescribers and the public.
FDA could also stand to benefit from the transparency associated with its actions, Moffit explained. The fewer postmarket regulatory actions it needs to take, the more intact its reputation remains. Better understanding about product risks might also better inform prescribing habits and public trust of a product, as physicians might be loath to prescribe a product off-label if its risks are known, and the public would have more realistic expectations about a product.
That being said, this theory has its critics. Discounting experts because of perceived financial ties would exclude many of the industry's best-qualified and most-knowledgeable people, thereby reducing the quality of advice available to regulators, for instance.
There's also no guarantee that FDA will actually use the advice of advisory committees, as they are not bound to its decisions one way or the other. And even if they are inclined to do so, the pressures of meeting decision dates as established in the Prescription Drug User Fee Act(PDUFA) might discourage regulators from acting upon that advice if it raises an issue that could be seen as being spurious-say, conflicted signals that a drug causes adverse cardiovascular events.
Is PDUFA Discounting the Value of Advisory Committee Decision Making?
Moffit's data, however, side primarily with those who find that transparency is advantageous to regulatory quality. Moffit looked at 565 drugs approved between 1986 and 2009, of which 224 were assessed by an advisory committee.
Those drugs that were given priority review status-granted to drugs which offer "major advances in treatment, or provide a treatment where no adequate therapy exists-were of particular interest to Moffit.
"Given the FDA's assertion that it consults with its advisors for its 'close calls' or its most uncertain cases, we expect a drug's priority status to be positively associated with advisory committee consultations," Moffit wrote.
Such drugs are often the first for a given condition, and are thus as seen as having a level of risk that is often beyond that of standard drugs, even if the drug is not itself novel.
Moffit's data showed this assumption to be correct. New Drug Application (NDA) submissions that were granted Priority Review Status were 3.75 times more likely to be sent to advisory committees for review than those not granted priority review status.
Also of interest: data suggest that "drugs reviewed after the introduction of deadlines are significantly less likely to receive pre-market advisory committee consultation than drugs reviewed before the deadline regimes began at the FDA," Moffit explained.
No other variable-not the novelty of the drug or prior approvals sought by the firm-accounted for advisory committee consultations, Moffit found.
The results are significant for a number of reasons, Moffit explained. "These results … lend support to FDA staffers' concerns that deadlines may impair the agency's ability to consult with advisors before reaching an approval decision."
And if drugs are being reviewed too quickly, the theory goes, then unsafe drug products might be making their way to market. But could the advisory committees be doing their job, even if they're doing so at a rapid pace? Could the other factors explored, such as the ability of the committee to raise issues into the public consciousness-be allowing for safer prescribing habits?
Do Safety and Transparency Go Hand-in-Hand?
To study this question, Moffit looked at a second set of data including safety information about products.
"The results suggest that, even when controlling for underlying drug risks, drugs that receive an advisory committee consultation are 2.5 times more likely to have a boxed warning added to their label after a pre-market review," Moffit found.
But a drug can have many risks, and Moffit raises another question in her piece: Did the advisory committees do a good job at identifying the totality of those risks?
Yes and no, Moffit found. "Results suggest that drugs reviewed by committees with no conflict of interest waivers were associated with significantly fewer subsequent drug safety alerts," Moffit wrote. "The quality or nature of the advice, this suggests, may matter to regulatory performance."
While the presence or absence of potentially conflicted individuals is unlikely to change the outcome of an advisory committee decision, her finding illustrates a more nuanced point: "There is much more to an advisory committee meeting than votes on product approval."
"Though advisory committees play only one part in perceptions of crisis, they remain crucial venues for facilitating the flow of information in and out of the FDA," Moffit continued. "They provide an accessible forum through which disease sufferers can call publicly on the agency to make therapies available more quickly, as the case of AIDS suggest. They can mark the start of public and scholarly attention to drug risks that would otherwise receive less media attention, and the publicity they generate can induce firms to reveal information they would otherwise not reveal publicly."
So is public advice and input a cure-all for what occasionally ails FDA? Not necessarily, Moffit said. The problem facing the agency-what she referred to as a broader "crisis of confidence facing the FDA"-"has its roots in agency structure, institutional designs and guiding policy."
"Public advice is only a partial antidote for the systemic challenges facing the agency," she concluded.