PDUFA V commitments signal a strong commitment to tolerance of open debate in the face of uncertainty.
I can admit to a rather powerful lack of enthusiasm when reading about interpersonal squabbles. It’s even worse in the scientific world: when I read about debates getting mired in personal attacks I tend to simply stop reading and move on to something else.
However, the really interesting part of this week’s meeting of an
FDA joint Advisory Committee to discuss the controversial diabetes drug Avandia – at least in the sense of likely long-term impact – is not the scientific question under discussion, but the surfacing and handling of the raging interpersonal battle going on right now inside the Division of Cardiovascular and Renal Products. So I'll have to swallow my distaste and follow along with the drama.
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Two words that make us mistrust Duke:
Anil Potti Christian Laettner |
Not that the scientific question at hand – does Avandia pose significant heart risks? – isn't interesting. It is. But if there’s one thing that everyone seems to agree on, it’s that we don’t have good data on the topic. Despite the re-adjudication of RECORD, no one trusts its design (and, ironically,
the one trial with a design to rigorously answer the question was
halted after intense pressure, despite an AdComm recommendation that it continue). And no one seems particularly enthused about changing the current status of Avandia: in all likelihood it will continue to be permitted to be marketed under heavy restrictions. Rather than
changing the future of diabetes, I suspect the committee will be content to let us slog along the same mucky trail.
The really interesting question, that will potentially impact CDER for years to come, is
how it can function with frothing, open dissent among its staffers.
As has been widely reported, FDA reviewer Tom Marciniak has written a rather wild and vitriolic assessment of the RECORD trial, excoriating most everyone involved. In a particularly stunning passage, Marciniak appears to claim that the entire output of anyone working at Duke University cannot be trusted because of the fraud committed by Duke cancer researcher
Anil Potti:
I would have thought that the two words “Anil Potti” are sufficient for convincing anyone that Duke University is a poor choice for a contractor whose task it is to confirm the integrity of scientific research.
(One wonders how far Marciniak is willing to take his guilt-by-association theme. Are the words “
Cheng Yi Liang” sufficient to convince us that all FDA employees, including Marciniak, are poor choices for deciding matter relating to publicly-traded companies? Should I not comment on government activities because I’m a resident of Illinois (my two words: “Rod
Blagojevich”)?)
Rather than censoring or reprimanding Marciniak, his supervisors have taken the extraordinary step of letting him publicly air his criticisms, and then they have in turn publicly criticized his methods and approach.
I have been unable to think of a similar situation at any regulatory agency. The tolerance for dissent being displayed by FDA is, I believe, completely unprecedented.
And that’s the cliffhanger for me:
can the FDA’s commitment to transparency extend so far as to accommodate public disagreements about its own approval decisions? Can it do so even when the disagreements take an extremely nasty and inappropriate tone?
- Rather than considering that open debate is a good thing, will journalists jump on the drama and portray agency leadership as weak and indecisive?
- Will the usual suspects in Congress be able to exploit this disagreement for their own political gain? How many House subcommittees will be summoning Janet Woodcock in the coming weeks?
I think what Bob Temple and Norman Stockbridge are doing is a tremendous experiment in open government. If they can pull it off, it could force other agencies to radically rethink how they go about crafting and implementing regulations. However, I also worry that it is politically simply not a viable approach, and that the agency will ultimately be seriously hurt by attacks from the media and legislators.
Where is this coming from?
As part of its recent PDUFA V commitment, the FDA put out a fascinating draft document,
Structured Approach to Benefit-Risk Assessment in Drug Regulatory Decision-Making. It didn't get a lot of attention when first published back in February (few FDA documents do). However, it lays out a rather bold vision for how the FDA can acknowledge the existence of uncertainty in its evaluation of new drugs. Its proposed structure even envisions an open and honest accounting of divergent interpretations of data:
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When they're frothing at the mouth, even Atticus
doesn't let them publish a review |
A framework for benefit-risk decision-making that summarizes the relevant facts, uncertainties, and key areas of judgment, and clearly explains how these factors influence a regulatory decision, can greatly inform and clarify the regulatory discussion. Such a framework can provide transparency regarding the basis of conflicting recommendations made by different parties using the same information.
(Emphasis mine.)
Of course, the structured framework here is designed to reflect rational disagreement. Marciniak’s scattershot insults are in many ways a terrible first case for trying out a new level of transparency.
The draft framework notes that safety issues, like Avandia, are some of the major areas of uncertainty in the regulatory process. Contrast this vision of coolly and systematically addressing uncertainties with the sad reality of Marciniak’s attack:
In contrast to the prospective and highly planned studies of effectiveness, safety findings emerge from a wide range of sources, including spontaneous adverse event reports, epidemiology studies, meta-analyses of controlled trials, or in some cases from randomized, controlled trials. However, even controlled trials, where the evidence of an effect is generally most persuasive, can sometimes provide contradictory and inconsistent findings on safety as the analyses are in many cases not planned and often reflect multiple testing. A systematic approach that specifies the sources of evidence, the strength of each piece of evidence, and draws conclusions that explain how the uncertainty weighed on the decision, can lead to more explicit communication of regulatory decisions. We anticipate that this work will continue beyond FY 2013.
I hope that work will continue beyond 2013. Thoughtful, open discussions of real uncertainties are one of the most worthwhile goals FDA can aspire to, even if it means having to learn how to do so without letting the Marciniaks of the world scuttle the whole endeavor.
[Update June 6: Further bolstering the idea that the AdCom is just as much about FDA's ability to transparently manage differences of expert opinion in the face of uncertain data, CDER Director Janet Woodcock posted this note on the FDA's blog. She's pretty explicit about the bigger picture:
There have been, and continue to be, differences of opinion and scientific disputes, which is not uncommon within the agency, stemming from varied conclusions about the existing data, not only with Avandia, but with other FDA-regulated products.
At FDA, we actively encourage and welcome robust scientific debate on the complex matters we deal with — as such a transparent approach ensures the scientific input we need, enriches the discussions, and enhances our decision-making.
I agree, and hope she can pull it off.]
