Live Blogging from FDA in the 21st Century Conference, Panel 3: Protecting the Public within Constitutional Limits

[Posted on behalf of W. Nicholson Price IIAcademic Fellow, The Petrie-Flom Center (with the disclaimer re: live blogging – see posts below)]

The third panel at the conference covered commercial speech protection and off-label drug promotion, in reaction to the Second Circuit’s December 12 case, United States v. Caronia.  Caronia was promoting Xyrem, approved for narcolepsy, for off-label uses, which is prohibited by FDA.  He was criminally charged and convicted, but the Second Circuit held this prohibition constitutionally suspect.

Leading off was Aaron Kesselheim.  Aaron started off describing the FDA’s prohibition on off-label promotion.  Off-label promotion prohibition is based on the requirement of substantial evidence for efficacy.  There are some safe-harbors, like distributing papers, but generally off-label promotion is prohibited because promotion drives prescription patterns, and off-label promotion for unapproved uses can have significant negative consequences.  FDA has negotiated many major settlements, totaling billions of dollars in recent years.  In this context, the Caronia decision is troubling from a public health point of view, even if not particularly surprising given the history of commercial free speech doctrine.

Aaron described four ways forward for the FDA after Caronia.  First, the government could rely more heavily on written materials as evidence, arguing that it is part of the label.  Second, the government could change the prosecutorial language, using speech as evidence of an attempt to misbrand, rather than prosecuting for speech; this might not be enough to fix the problem.  Third, the government could prosecute off-label promotion as false and misleading speech, but that requires hard case-by-case evaluations.  Fourth, the government could better argue that the Central Hudson test for commercial free speech is met.

Next, Chris Robertson also took Caronia as a jumping-off point, noting that Caronia was actually convicted of conspiracy to introduce a misbranded drug into interstate commerce – though the Second Circuit held he was actually convicted for his speech.  Caronia comes in the wake of robust First Amendment jurisprudence from the Supreme Court, including Citizens United, Sorrell, Stevens, Alvarez, and Fox v. FCC, and thus might be a harbinger of this reasoning spreading across the country.  In addition, the reasoning of Caronia could potentially apply equally to drugs with no approved use, and thus undermine the entire FDCA (since what is defined as a drug is determined by label claims).

Chris focused on the fact that Caronia revolves around the truth or falsity of claims made, but in this case, the government didn’t even argue that the speech at issue was false.  In other contexts, truth has been described as necessary for First Amendment protection.  So the question arises: is the speech in Caronia true?  Caronia made many claims, and nobody knows the truth of most of them – the scientific testing hasn’t been done.  So the next question becomes: is belief warranted in the absence of proof?  Presumptions can be based on epistemic (source expertise minus bias) or institutional bases.  Drug salespersons likely have little expertise and lots of bias – not a credible source on epistemic grounds.  On institutional grounds, the FDCA exists because the cost of errors is high, but it’s not rational for individuals to invest in proving whether a drug works; but the patent system allows the drugmaker to capture benefits and internalize the costs, and that with the FDCA, the drugmaker has to prove it.  So the question is whether judges should presume truth in the absence of epistemic warrant?  Judicial presumptions that the plaintiff has to prove falsity only really applies so far for media defendants; otherwise, the defendant can use the First Amendment as a defense.

Chris’s final claim is that courts can take a third position, and stay truth-agnostic in situations like this.  This gives firms two bites at the apple: they can prove to FDA they’re telling the truth, or to a jury in a trial.

Finally, Jessica Flanigan wraps up the panel with a presentation on patients’ rights related to Caronia.  She argued that Caronia was correctly decided, and a good thing, because more off-label marketing should be allowed.  And contrary to FDA’s current statements, Caronia should make us rethink the drug approval process.

Jessica started out with the argument that Caronia was correct.  It’s unclear that off-label communication should be regarded as misbranding, especially since courts have been moving away from regulation of commercial speech.  Under Central Hudson, the court should have questioned whether FDA regulation of off-label speech is actually in the interest of public health; FDA didn’t show that.  It’s hard to reconcile FDA’s allowing off-label prescribing but prohibition of off-label promotion.  And off-label promotion restrictions don’t actually advance state interests; they might actually cost lives.  For instance, it took a while to know that beta-blockers could prevent second heart attacks, and that information was slow to circulate, since it spread only among physicians.  It took 7 months for manufacturers to get label expansion, which delay likely resulted in a 4,000 deaths from second heart attacks.  In addition to the possibility of harms, we should look at the benefits of more-informed patients getting access to drugs.  Restrictions can also reduce institutional trust and relationships, as doctors and companies are wary of interacting and sharing information.  Finally, physicians and patients are both entitled to additional information.

Jessica continued with how FDA should change its drug approval framework in light of Caronia.  Now, a drug must be proven for one condition – but after that, it can be used for any condition.  The only reason to prove efficacy requirements for other conditions is to broaden label promotion, but under Caronia, there’s no need for that.  Jessica argued, as she does in other works, for a safety-only approval standard, without an efficacy requirement.  This could promote more innovation, and will also reduce the drug-approval lag, citing Abigail Alliance.  In addition, patients have rights to access medicine, and FDA might not even be in the best epistemic position to make decisions on efficacy, since the cost-benefit analysis is an individual analysis, rather than one based on the chemical properties of the drug.  That’s an individual policy judgment, not a uniform judgment.  This is why off-label drug uses are a good idea.  People can take FDA approval into account, but can decide it’s not dispositive for them.  Thus, for this reforming role, as well as for the free-speech and information-flow reasons, Caronia was correctly decided and a positive decision as the first step toward greater patient empowerment.

Moving onto Q&A:

Glenn Cohen asked Chris and Aaron about whether settlements are so dominant that the Caronia question is unlikely to be litigated.

Chris answered that there was a sense of the court that Mr. Caronia was getting picked on – but bad facts make bad law, and the holding is a broad one.  He thinks that settlements will be negotiated quite low – it’s hard to hold industry’s feet to the fire after Caronia.  Aaron agrees.

Alta Charo asked Jessica about a safety-only standard; since safety isn’t an absolute number, how do you balance safety against benefit if we’re not going to have effectiveness data?  Why would have any approval process without that balancing?
Jessica replied that maybe yes, even quite dangerous drugs should be available if patients think they’re worth it.  Safety standards might be necessary for the prevention of fraud, so that companies need to disclose the effects of drugs.  Some minimal premarket prohibitions are still warranted, but much less than exist now.

Lewis Grossman mentioned Judge Chin’s tricky moves.  The substantial interest of preserving NDA to preserve patient interests was disaggregated into two parts, and then comes up with more ways to protect patients than preserving NDAs.  Another tricky move is talking about other things the government can do, but lots of those are things FDA can’t do.  But the question is: if Caronia hadn’t mentioned many uses, but had just stated that Xyrem was in Phase III clinical trials for fibromyalgia, which suggested efficacy.  Why shouldn’t drug companies be able to inform doctors about that fact?
Aaron answered that information from ongoing trials isn’t reliable until the studies are done, and with the power that drug companies exercise over doctors, that’s a big risk.  But in no cases that he listed were the essential elements of the case legitimate scientific facts – they were all puffery and exaggeration and underestimations.  Chris added that the case-law treats misleading speech like untruthful speech.  But for him it matters.  And whenever a drug promoter is talking about a use, he’s implying it’s safe and effective.

John Young with FDA asked Aaron and Chris about free speech implications of Caronia radiating out from drugs to other parts of FDA. Chris answered that this does seem more broadly applicable than drugs.

Lesley Francis noted the implications of Jessica’s brave paper that it’s nice to have lots of information, good and bad, but there’s no constitutional doctrine requiring people to speak.

Jessica thinks that FDA’s approval can still be a useful piece of information, which doctors can use.  If we really think physicians are so gullible that they are swayed by drugmakers, we should rethink physicians’ epistemic authority as gatekeepers.Tom McLean, addressing Jessica’s paper, noted that the problem of iatrogenic injury is missing.  When you turn things loose off-label, those injuries increase.  He also noted that off-label use drives up health-care costs, for which the government pays a fair share, and asked for comments.

Jessica answered that the fact that you provide someone with a public health benefit entitles you to violate that person’s rights.  Just because we pay the price for people’s bad choices doesn’t entitle us to limit their decisions.

Rachel Sachs asked Chris about the jury trial aspect of the piece, wondering whether drug companies will think juries are more sympathetic than FDA, and the preclusive effect of sympathetic rulings.

Chris responded that he shares worries about juries, but Daubert can help police those issues.  Aaron thinks that fighting Caronia is better than trying to police these issues later.

And that’s it for Caronia today?

The Petrie-Flom Center Staff

The Petrie-Flom Center staff often posts updates, announcements, and guests posts on behalf of others.

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