Biosimilars, Biostatisticians, and the New EEU

There are very few days during which the worlds of drugs and medical devices are entirely quiescent, thanks to very active American courts and international regulatory churn. There is some good news in all this, but how good is it?

If you’re in the biosimilars business, the latest news is quite good, indeed.

SCOTUS rules for Sandoz

The U.S. Supreme Court ruled on June 12 that makers of biosimilars do not have to wait six months after the issuance of a biologics license application to begin marketing that product, a development that could bring some less costly biotech drugs to market more quickly and possibly take a bite out of spending on these agents.

In a 9-0 vote, the Court ruled in favor of Sandoz in Sandoz v. Amgen, a case that made a stop at the Court of Appeals for the Federal Circuit, where the outcome was quite different. Sandoz had argued that the terms of the Biologics Price Competition and Innovation Act of 2009 had essentially worked to add half a year of exclusivity to the 12 years already granted by the statute, and by some accounts, Sandoz’s Zarxio is about 15 percent less expensive than Amgen’s Neupogen, a drug for chemotherapy-induced neutropenia.

The news might not change the field dramatically in the near term, given that the FDA has approved only about half a dozen biosimilars to date, but one possible candidate for a quick entry to market is an oncology biosimilar for Avastin, which will undergo an FDA advisory committee review in mid-July. In an ironic twist, Amgen teamed up with Allergan to produce this biosimilar.

Expert witness refuted in Zoloft lawsuit

Pfizer scored a victory in the running lawsuit pertaining to the company’s flagship antidepressant Zoloft, but what may have been the most interesting part of this story is that a court rejected expert testimony relating to allegations that the selective serotonin reuptake inhibitor (SSRI) causes congenital heart defects.

The decision may have brought to a close an effort by more than 300 litigants, which absorbed a second consecutive negative outcome in the U.S. Court of Appeals for the Third Circuit. Both the appeals court and a district court decreed that the expert witness, Nicholas Jewell, a biostatistician at the University of California at Berkeley, had failed to plausibly link the drug to the birth defects. Among the problems with Jewell’s presentation is that he had rejected meta-analyses he had previously cited in a separate lawsuit pertaining to another SSRI.

Whether the plaintiffs will take this lawsuit any further is difficult to forecast, but a footnote on page 10 of the Appeals Court decision remarked that the plaintiffs’ attorneys had conceded that they are “unable to establish general causation” if the courts jettisoned Jewell’s testimony. Summary judgment was granted in favor of Pfizer.

This is not the only multi-district litigation keeping attorneys at Pfizer busy, however. A very active set of lawsuits dealing with proton pump inhibitors and purportedly associated kidney damage would seem to implicate the OTC version of Nexium, marketing rights for which Pfizer picked up five years ago in a deal with AstraZeneca. The U.S. Judicial Panel on Multidistrict Litigation (JPML) declined in January to consolidate these lawsuits, but another motion for consolidation has been filed by attorneys with Seeger Weiss of New York.

Regulations, regulatory agreements on the move

Efforts to ramp up medical device regulatory schemes in outside-U.S. jurisdictions are nothing new, but device makers can add Malaysia and the Eurasian Economic Union (EEU) to the list of national and international entities diving into deeper regulatory waters. The news for device makers is somewhat mixed, but greater clarity alone is sometimes enough to overcome other considerations.

First, Malaysia’s Medical Device Authority has declared that adverse events associated with medical devices will have to be reported to the agency within 30 days. This apparently applies to all devices that are on the Malaysian market, regardless of where the adverse event took place. Any fatalities have to be reported within 10 days, and device makers have a mere 48 hours to advise the agency of any problems that might carry a public health consideration.

The EEU continues to work toward a single market for drugs and devices, a move which if successful would capture the markets of Russia and four other nations for a total 2015 population of nearly 184 million. There are reports that Tehran is interested in a free trade agreement with the EEU, although there is no indication that Iran would take part this new med tech regulatory bloc despite the deepening geopolitical ties with Moscow. Serbia is likewise said to be interested in doing business with the EEU, but it’s not clear whether Belgrade has full-blown membership in mind, either, although the protracted and difficult negotiations for entry into the European Union might strike some as suggestive.

To date, the EEU regulatory regime lacks several critical documents, such as a framework for quality management systems. Registration requirements for this international regulatory system would be phased in over the next four years, however, giving industry a little breathing room for offerings already available in this market.

Of Combo Products and High Courts

Tourists to our nation’s capital can always find plenty to do, and the same can be said for those in the life sciences with an ear for crucial policy matters. Following are two items of interest to makers of FDA-regulated products, one of which may have a significant influence over FDA regulation over an increasingly important class of medical products, while the other addresses federal prosecution under the responsible corporate officer doctrine.

Misgivings regarding the FDA’s CPPC

The FDA’s Combination Products Policy Council (CPPC) has a pretty serious lift in front of it, not the least of which is the thorny problem of differences in culture and attitude at the various centers that will be caught up in these combo product applications.

For some time, it has been known that many reviewers at the Center for Drug Evaluation and Research are no fans of the 510(k) program, apparently seeing it as an unforgivably fast track to market. Of course, the notion of substantial equivalence is a stranger in a strange land at CDER, which might explain a lot of the antipathy toward 510(k) devices there.

The agency opened a docket at regulations.gov in January, seeking feedback on topics the CPPC might address, and as might be expected, some of the consternation has to do with the process for determining a combo product’s primary mode of action. One concern in particular is how the agency will go about determining what sort of evidence will be needed to establish a product’s PMOA.

Other concerns relate to procedures for handling inter-center disputes regarding PMOA when the Office of Combination Products seems unable to broker a conflict. On the other hand, some have indicated that the interactive review process at CDER is more cumbersome than at the Center for Devices and Radiological Health, and thus would add time to what already promises to be a difficult review process.

One issue that was not conspicuous in comments to the docket was that of user fees. A sponsor will obviously have to pay more if the product’s PMOA is declared to be that of a drug, but what about fee sharing between centers? Will the lead center share user fees with the other center or centers? That’s not clear, and while reviewers at CDRH might find the drug user fees more than adequate, reviewers at CDER might find the device fee schedule unacceptably miserly.

SCOTUS says no to DeCoster

In one of the more interesting Park doctrine cases of recent vintage, the Supreme Court has opted not to hear arguments in the case of Decoster v. U.S., which allows to stand a three-month jail sentence imposed on the father-son ownership team in the egg business.

Many members of the bar see DeCoster as an outlier in that it entailed a jail sentence for Jack and Peter DeCoster, who are said to have been unaware of the violative behavior going on at their company, but more important is the prospect that this case will serve as a precedent for federal prosecutors who want to imprison those in the food, drug and device industries for problematic products. The high court’s decision to pass on the case means the two men will serve their jail sentences, but it also suggests that the Supreme Court will not hear this case until an appeals court other than U.S. Eight Appeals renders a different verdict in a similar case.

It may be an odd source of comfort to note that federal prosecutors will likely try out this new enforcement tool fairly promptly, which suggests that a different appeals court will have a crack at this question in fairly short order. Understandably, nobody in the food, drug or device business wants to serve as the subject of that case, but industry as a whole might want to see this question resolved as quickly as possible.

There is some question as to whether the current composition of the Supreme Court makes this the ideal time to take up such a case, but it’s difficult to predict which of the justices will be the next to leave the Court. Ruth Bader Ginsberg is a leading candidate for retirement because of her age (84), but Anthony Kennedy is no kid, either, as his 81st birthday is fast approaching. A Trump administration replacement for Ginsburg would seem to guarantee DeCoster will be overturned, but those in search of a predictable legal environment might say sooner is better, regardless of the prospects for churn at 1 First St. NE in our nation’s capital.

Petition for Cert Revisits Park Doctrine

Those in the life sciences need little or no explanation regarding the implications of Park doctrine, but this relatively relaxed threshold for federal criminal prosecution may soon undergo a scrub-down at the Supreme Court of the U.S. Whether the Court will conclude the time is ripe to revisit Park doctrine is tough to predict, particularly since the acting Solicitor General has argued that this case deserves none of the Court’s attention. Nonetheless, there is a new justice at the Supreme Court, one whose track record suggests a degree of skepticism about deference to the federal government’s position on legal matters.

Jail time at heart of debate

The case of Decoster v. U.S. revolves around a three-month jail sentence imposed on the father-son team of Jack and Peter DeCoster, whose Quality Egg LLC company was charged in connection with an outbreak of Salmonella in 2010. The DeCosters agreed to pay personal fines of $100,000 each, and Quality Egg gave up nearly $7 million as well.

Prosecutors were unable to offer evidence that the DeCosters were aware that the company was shipping tainted eggs, and thus the three-month sentence imposed in the district court hearing is seen as a break with routine sentencing practice under Park doctrine. The district court judge concluded that the duo had acted negligently, and the U.S. Court of Appeals for the Eight Circuit upheld the jail term by a 2-1 vote. Subsequently, a request for an en banc hearing at the Eight Circuit was denied, whereupon counsel for the defendants petitioned the Supreme Court to take the case.

In response to the petition, acting Solicitor General Jeffrey Wall argued that the petitioners had effectively waived “any challenge to the statutory basis for their convictions” with their guilty pleas in district court, a state of affairs that carried over to the appeals court proceedings. Wall is unlikely to hold onto the job, given that the White House has named Noel Francisco, formerly a partner at Jones Day, as the administration’s pick for the position. Little or nothing has happened since the White House mentioned Francisco, however, so it may that Wall’s is the only name from the Solicitor General’s office the Supreme Court will hear in connection with DeCoster before deciding whether to grant cert.

WLF cites ‘disturbing trend’ in federal cases

In marked contrast to the position staked out by the federal government, the Washington Legal Foundation – no stranger to controversies surrounding federal prosecution of FDA-regulated entities – has written in support of a Supreme Court review, citing a “disturbing trend at the federal level to criminalize normal, everyday business decisions.” WLF argued that the prison sentence “vastly expands the scope of the Park doctrine beyond constitutional limits,” and that should this outcome develop into a trend, “it will become intolerably risky to be an executive in the food and drug industries” in the U.S.

Also on record with a friend-of-the-court brief is the National Association of Criminal Defense Lawyers, but that may not be the last of the organizations that will weigh in on this matter. The Pharmaceutical Research and Manufacturers of America and the Cato Institute both made their opposition to the jail term known as the case made its way through the lower courts, a clear sign that this case has piqued the interest of a wide range of stakeholders.

Companies in the life sciences will certainly want to track this case closely, particularly since the confirmation of Justice Neil Gorsuch to the bench would seem to suggest that the Court would at least be open to the notion that the district court was out of bounds in imposing a jail sentence. There is little to indicate that Gorsuch has a track record in Park doctrine cases, but he has exhibited a willingness to question the practice of judicial deference to the positions staked out by the executive branch. That skepticism on Gorsuch’s part offers some hope that the Court will not simply accept at face value the Solicitor General’s opinion that this case merits no review.

Multi-district Litigation; (Lack of) Evidence and Pending Legislation

Multi-district litigation (MDL) has its advantages even for defendants, but some see abuses, including a recent case involving an orthopedic device maker’s metal-on-metal hip implants. There is legislation in circulating on Capitol Hill that might address some of the problems associated with these mass actions, but the Trump administration and the House GOP have their hands full, raising the prospect that any corrective legislation might languish.

No evidence? No problem
Device maker Biomet faces an MDL case that took a new twist recently when a judge in Indiana dismissed the defendant’s motion to dismiss the claims of six plaintiffs in the product liability suit. A pretrial order filed in 2013 had required that plaintiffs find some means of preserving the device components in order to be eligible for the action, and several of the plaintiffs indicated that health care practitioners either refused or failed to send the devices along before the MDL commenced. One of the plaintiffs managed to recover the device and kept it in a plastic bag in a closet, but made no mention of this until she was deposed.

Judge Robert Miller of the District Court for the District of Northern Indiana decreed that the five plaintiffs who never recovered their devices could not be excluded from the MDL because those explants took place prior to the start of the MDL. Biomet’s attorneys argued spoliation as a cause for dismissal of these plaintiffs, but Miller expressed the view that these litigants could not be excluded because there was no demonstration of bad faith on their parts. As for the sixth plaintiff, her failure to handle the device appropriately seemed to have no effect on her eligibility for the MDL due to an absence of any indication that her failure to disclose her possession of the article was anything more than an oversight.

Courts are said to have considerable leeway in determining when spoliation sanctions should be applied, but defendants may be concerned that Miller’s determination could dilute the value of spoliation. There is also the lingering question of the circumstances in which a device maker is liable for devices that are made unavailable for examination because they are disposed of prior to the start of an MDL procedure.

Spoliation not mentioned, but …
The Fairness in Class Litigation Action Act of 2017, sponsored by Rep. Bob Goodlatte (R-Virginia) has made its way into the House and Senate Judiciary Committees. The bill states that among its purposes is to “diminish abuses in class action and mass tort litigation that are undermining the integrity” of the legal system.

While the bill does not seem to directly address spoliation, section 5 of the bill specifically calls out MDLs. This portion of the legislation would require that plaintiff’s counsel offer evidence in support of the claim of injury as well as “the alleged cause of that injury.” The filing of such information must take place within 45 days of the transfer of the legal action or be “directly filed in the proceedings.” Should that information not show up in the judge’s hands within the following 30 days, that plaintiff is excluded, and the bill states further that these deadlines “shall not be extended.” The text says little about what would constitute evidence in support of a claim of injury, however.

Another interesting feature of Goodlatte’s bill is that it limits attorney fees to 20 percent of the monies recovered, and any disputes about this provision would be handled by the judge who handled the pretrial proceedings. Whether this feature will tamp down some of the legal adventurism said to characterize MDLs is up for grabs, but corporate attorneys can’t help but cheer this feature (and others) of this legislation.

And despite the distractions posed by health care and tax reform, the presence of a GOP majority on both sides of Capitol Hill offers the most favorable conditions for tort reform of any kind than have been seen at any time in the past decade, particularly since a Republican holds the Oval Office for the first time in eight years.

Judge Says Device Makers Must Warn Hospitals

Device makers know all too well about the need to notify providers of the hazards associated with their devices, but a new case in the Pacific Northwest would expand that liability to hospitals, seemingly destroying the learned intermediary doctrine in the process.

Intuitive Surgical, maker of the groundbreaking da Vinci surgical robot, was on the losing end of a lawsuit in the Washington State Supreme Court recently, which declared that the device maker is liable for notifying hospitals about the risks attached to the device’s use. The case, Taylor v. Intuitive Surgical, Inc., involved the da Vinci’s use in prostate surgery, and the decision from a state circuit court hearing said the surgeon acknowledged that the patient, the late Fred Taylor, was overweight and thus not a good candidate for the procedure using the da Vinci.

Trial, appeals courts exonerate Intuitive

The treating physician, Scott Bildsten, was performing his first non-proctored procedure with the da Vinci and informed Taylor that he (Bildsten) lacked the experience needed to conduct the procedure on obese patients. The patient was in the operating room for 15 hours while Bildsten switched from the da Vinci to open prostatectomy, following which the patient was in intensive care for 20 days. Taylor died four years later in 2012.

The jury trial determined there was no liability for Intuitive despite that the plaintiff’s attorney recommended that the jury be instructed that the device maker had a duty to warn Harrison Medical Center, a decision with which the appeals court agreed. The state high court decreed, however, that the physician “is often not the product purchaser,” and thus state law mandates that device makers inform hospitals “about their dangerous medical devices,” a passage penned by Justice Susan Owen.

Owen determined that the trial court had erred in its failure to instruct the jury that the device maker was legally required to inform the hospital of the hazards associated with the da Vinci, and remanded the case to the trial court. Owen acknowledged, however, that Harrison Medical Center was in the practice of providing credentials on the da Vinci after only two proctored procedures while other establishments in the state required three or more proctored procedures prior to credentialing.

 

Nonetheless, Owen said the learned intermediary doctrine was not applicable because the Washington Product Liability Act (WPLA) “imposes a separate and distinct duty” on the device maker to inform the hospital of any risks. She cited language from the dissenting opinion in the appeals court case, said to state that while a physician is the gatekeeper between the manufacturer and the unwarned patient, the physician is not the gatekeeper between the patient and “the unwarned hospital” (italics hers).

Owen asserted further that a hospital’s duty to ensure a device is safe is separate from that of a physician despite that a preceding case had determined that a pharmacist does not have a duty separate that from a prescribing physician, a reference to the 1989 decision in McKee v. American Home Products., another case specific to the Evergreen State.

Lone dissenter in en banc decision

Owen’s decision was backed by five other justices who took part in the en banc hearing, but Justice Barbara Madsen dissented, stating that Intuitive was indeed liable for informing a hospital as to the hazards entailed in the da Vinci’s use. Madsen asserted, however, that the wife of the deceased “cannot invoke a duty owed to Harrison to recover damages.” She noted that several steps stood between the widow and the device maker, starting with the sale of the da Vinci to the hospital, Harrison’s credentialing of Bildsten, and Bildsten’s use of the device on the patient. Madsen stated further that the widow of the deceased had already obtained a settlement from Harrison, which would eliminate any further claims arising from Harrison’s credentialing of Bildsten.

Among those providing briefs to the court was the D.C.-based Medical Device Manufacturers Association, which might mean nothing more than that the association sees this as a critical issue in the state of Washington. The reader may find it interesting that this same court recently found that the WPLA also truncated federal preemption of state law, although this was in the context of aviation law (see Estate of Becker v. Avco Corp.).

One cannot rule out the possibility that other states might amend their statutes to reflect the elements of the WPLA that proved pivotal in the case against Intuitive – and in any event, some would argue there is no shortage of jurisprudential adventurousness – but the message here is at least that the state of Washington presents much more legally hazardous terrain than is perhaps widely appreciated.

Not-So-Good Manufacturing: GMPs and Alleged False Claims

The use of violations of good manufacturing practices as a pretext for False Claims Act prosecutions is not unprecedented, but it is not commonplace, either. Baxter Healthcare has agreed to pay a total of roughly $18.2 million dollars in connection with just such a legal pretext, but the precedent is much more important than the dollar value of this case.

The settlement agreement between Baxter and two government entities, the Department of Justice and the Department of Veterans Affairs, stipulates that Baxter will pay $2.16 million to settle the whistleblower suit, which alleged that the company violated current good manufacturing practices in the production of products such as Ringer’s lactate solution between January 2011 and December 2012. The agreement noted that the relator received roughly $430,000 for his troubles, a sum that may or may not make up for any future employment difficulties.

Baxter also had to hand over $16 million as part of a deferred prosecution agreement, but the Jan. 12 notice by the Department of Justice acknowledged that there were no adverse events reported in association with the purported mold found in a processing facility for the products in question.

To be sure, this is not the first instance in which a company had to face a legal action related to GMPs and relator claims. A previous episode of this sort arrived at the U.S. Court of Appeals for the Fourth Circuit, which ruled in February 2014 that allegations of failure to comply with the regulations did not suffice to support a claim of violation of the False Claims Act. Omnicare may have dodged a bullet in this instance, but there were no allegations that the company attempted to deceive the FDA, an allegation that fed the $500 million settlement between India’s Ranbaxy and the FDA in 2013.

Clearly Baxter has no intent to pursue the case further, and the company enjoys a market cap of nearly $27 billion, so the loss of $18 million might come across as a rounding error in the company’s financials. It is not clear whether this leveraging of GMPs to feed allegations under the False Claims Act is an aberration or the leading edge of a new trend. One consideration is the volume of warning letters the FDA issues in connection with drug and device manufacturing as a source of fodder for these qui tam suits, which the DoJ rarely turns down.

Another thing to consider is that the world of drug sterility and environmental monitoring may have changed after the 2008 episode involving tainted heparin from China. More recently, the pharmaceutical industry has a public relations problem stemming from recent pricing debacles, and the medical device industry has been dinged over the power morcellation and permanent-birth-control device sagas. Those in the life science industries have to recognize that they have little leeway in the court of public opinion, a fact which all too easily translates into no leeway at all in the court of law.

Inspection imbroglio spurs legislation

There is never a shortage of new bills floating around on Capitol Hill, but Sens. Johnny Isakson (R-Ga.) and Michael Bennett (D-Colo.) have introduced legislation that would force the FDA to finally live up to its purported risk-based approach to device inspections, a bill that seems destined to appear in the legislation for the next device user fee agreement.

Recall that the current user fee agreement, MDUFA III, expires at the end of September, hence the need for a new five-year handshake. The fourth iteration calls for just shy of $1 billion over the five-year term, quite a bit more than the $595 million agreed upon in MDUFA III.

The bill by Isakson and Bennett addresses grievances of some standing regarding FDA inspections of device manufacturing sites located in the U.S. Industry has for some time complained that the agency is far more likely to give sites located outside the U.S. a heads-up when an FDA filed investigator is on the way, but device makers have also claimed that FDAers are sometimes late for domestic inspections, and in some instances, don’t show up at all. Other issues include poor communication from the agency regarding the acceptability of corrections made by companies in response to inspectional findings, which if valid would help explain why the FDA’s warning letter close-out program has been an abject failure.

The overarching goal of the bill, however, is to force the agency to focus more on sites that have a sketchy compliance history and less on sites that have a clean quality systems record. Whether the drafting of this bill is a signal that Congress is confident that the user fee agreement can go forward despite the Trump administration’s moratorium on federal hiring is not clear.

Medtronic beats express warranty claim

Attorneys at Medtronic seem to have all the experience where PMA preemption cases are concerned, but Wildman v. Medtronic worked out well for the company, which has not always been the case. The plaintiff in this case, Ray Wildman, had a Medtronic neurstimulator implanted to deal with pain, and the unit’s battery quit after less than two years despite that the company’s website had claimed that those devices had an expected life of nine years.

The suit relied on the warranty implicit in the company’s website for the RestoreUltra neurostimulation unit, which states in part, “the result of extensive design and testing involved in manufacturing rechargeable neurostimulators give Medtronic the confidence that our device is reliable for 9 years.”

That statement is still on Medtronic’s website, so one imagines that the FDA is aware of the statement, and hence has no issue with it. From there, one has to assume that the statement is backed by some evidence, otherwise the agency would have forced Medtronic to pull the statement by now.

In the end, Judge David Ezra of the U.S. District Court for the Western District of Texas dismissed the case with prejudice, in part because Wildman’s suit would impose requirements that are “different from, or in addition to” the FDA-imposed requirements that were part of the PMA for this device. Chalk up one for PMA preemption.

FDA’s Interesting Off-Label Memo

 

The FDA recently posted a memorandum spelling out the agency’s views regarding off-label promotions, a document chock full of interesting observations. This discussion is now taking place in a somewhat different political backdrop, however, particularly in light of the dismissal of a high-ranking and well-known member of the Department of Justice. The picture in aggregate is highly fluid – which may or may not portend change – but which nonetheless is almost certainly unsettling to those at the FDA who prefer the status quo where off-label promotion is concerned.

When a solution is not a solution

The January 2017 FDA off-label memo offers the expected rationale for the agency’s current views on commercial speech, including that the requirement to conduct studies of a drug or device for a specific indication does a lot to provide assurance that the therapeutic in question will do more good than harm.

The memo takes a turn for the peculiar, however, when the FDA takes credit for things such as patent protection, which most would say redounds to the credit of the statute and the Patent and Trademark Office. Subsequently, the memo offers alternatives to the current state of affairs, such as a ban on off-label use of drugs and devices, and the application of a higher level of taxation on off-label use.

The problem with these and a couple of others of the FDA’s alternative commercial speech universes is that they are entirely outside the agency’s jurisdiction. For instance, it is quite well known that off-label use is within a physician’s discretion, and doctors are not regulated by the FDA. Not yet, anyway. As for tax policy, there’s no need to explain why this is outside the agency’s statutory authority.

There are several items of interest where context is concerned, not the least of which is that Robert Califf has resigned from the FDA commissioner’s chair, leaving the Trump administration with a very interesting job to fill. A number of names have been floated for that opening, including that of Scott Gottlieb, whose curriculum vitae includes a stint as one of the FDA’s deputy commissioners. Gottlieb has voiced reservations about the agency’s standards regarding off-label speech, but other candidates of record, including venture capitalist Balaji Srinivasan, are unknowns where the off-label discussion is concerned.

All in all, attorneys at the FDA have to assume the commercial speech question is likely to weigh against the agency in the months and years ahead, even if nothing in the way of legislation surfaces.

More than one new face at DoJ

One interesting bit of context here is the dismissal of Sally Quillian Yates, she of the famed Yates memo, which some believe comes up only a little short of the extortive tenor of the Thompson memo. President Trump gave Yates the axe for announcing that DoJ would not mount a legal defense of the administration’s executive order on immigration from six nations said to harbor terrorists. Whatever one believes about that executive order – and it should be noted that recent developments do not necessarily portend a revisitation of the memo that bears Yates’ name – her dismissal sends an unmistakable signal that employees of the federal government can press their luck only so far.

Clearly it’s too early to anticipate what will become of the off-label discussion, but this issue has occupied a tremendous amount of time and effort at the FDA, and these developments can’t help but embolden adversaries of the agency’s current stance on the commercial speech/First Amendment question. Change may or may not be in the offing, but it needn’t start with the executive branch of the federal government. It may come in the courts, and whomever the Trump administration appoints to the job of solicitor general may have some very interesting things to say, indeed, if the matter ever reaches the Supreme Court.