The Off-Label Divide

The Food, Drug, and Cosmetic Act (FDCA) regards a drug “misbranded” if its label does not bear “adequate directions for use.” 21 U.S.C. ' 352(f). This means that the label of a drug must reveal “all conditions, purposes, or uses for which such drug is intended, including [those] suggested in its oral, written, printed or graphic advertising.” 21 C.F.R. ' 201.5(a). Since the FDA approves all labeling of prescription drugs, the use of a drug for any purpose other than those spelled out on its label (those for which it and its labeling were approved) is an “off-label” use and therefore prohibited.

The FDA does not, however, regulate physicians, who may legally prescribe drugs for off-label use. As a result, most sources agree, off-label use of drugs is widespread. According to a Government Accounting Office Study in 1991, 56% of cancer patients reported use of off-label prescriptions while 33% of all prescriptions in cancer treatment were off-label. A survey of AIDS patients ascertained that 81% had received at least one off-label medication, while 40% of all reported drug use by AIDS patients was off-label. Another survey revealed that nearly all pediatric patients receive off-label medications. Similarly, a majority of antidepressant usage was found to be off-label. In yet another survey, all dermatologists answered that they commonly wrote off-label prescriptions. Finally, a survey of pregnant women found that 23% had taken at least one drug off-label during their third trimester. Tabarrok, “Assessing the FDA via the Anomaly of Off-Label Drug Prescribing,” The Independent Review, v. V, n. 1, 25 (2000). As one commentator put it, “off-label use is legal, common, and necessary.” Beck & Azari, “FDA, Off-Label Use, and Informed Consent: Debunking Myths and Misconceptions,” 53 Food & Drug L. J. 71, 72 (1998).

So, although manufacturers are prohibited by the FDCA from promoting drugs for off-label use, physicians may prescribe drugs off-label as they please. If manufacturers breach the FDCA rule, they can be sanctioned with harsh civil and criminal penalties, including felony charges. 21 U.S.C. ' 333(a); 18 U.S.C. ' 3571. The burning issue is this: May manufacturers be held liable for violations under tort theories or is civil liability for injury preempted by the FDCA?

Preemption

The Buckman line of cases really begins more than a decade ago with Cipollone v. Liggett Group Inc., 505 U.S. 504 (1992). In Cipollone, plaintiff filed suit against cigarette manufacturers under a number of theories, including strict liability, fraud, negligence and breach of express warranty. The manufacturers argued that two federal labeling statutes expressly preempted all the plaintiff's claims. The first of these statutes stated that “no statement relating to smoking and health shall be required” as long as cigarettes are labeled in accordance with the provisions of the statute. 15 U.S.C. ' 1334 (1965). The second superceded the first and stated that “no requirement or prohibition based on smoking and health shall be imposed under state law” to cigarettes labeled in accordance with the provisions of the statute. 15 U.S.C. ' 1334(b) (1970).

The U.S. Court of Appeals for the Third Circuit found both preemption provisions ambiguous but found a broad implied preemption encompassed by congressional intent. Cipollone v. Liggett Group Inc., 789 F.2d 181, 188 (1986). The U.S. Supreme Court rejected this analysis, holding that an implied preemption analysis is unwarranted where a germane express preemption provision exists. It found that Congress had limited the law's express preemption to advertising and labeling, leaving most common-law tort claims viable.

Then, in Medtronic Inc. v. Lohr, 518 U.S. 470 (1996), the Court found that the express preemption statute in the 1976 Medical Device Amendments (MDA), 15 U.S.C. ' 360C, to the FDCA did not preempt state law claims against a manufacturer of a Class III medical device approved under 510(k) of the Food Drug and Cosmetic Act (21 U.S.C. 360(k)). The Medtronic pacemaker at issue had been approved under 510(k), a provision that accelerates the approval process for medical devices “substantially equivalent” to products already approved. 510(k) is therefore an exception to the rigorous pre-marketing approval (PMA) process whereby safety and efficacy must be categorically demonstrated. The preemption provision of the MDA stated that no state could impose requirements different from or in addition to those imposed by the FDCA “relate[d] to the safety or effectiveness of the device.” 15 U.S.C. ' 360k(a). Because FDA regulations leading to approval of the device under 510(k) focused on equivalence rather than on safety and efficacy, state law that established requirements for safety and effectiveness were not preempted. The Court did not analyze the Medtronic case under a theory of implied preemption, nor did the Court address the fate of Class III devices approved under the rigors of the PMA process.

In Buckman, the Court looked at bone screws in a product liability context. Buckman Company had assisted the bone screws' manufacturer, AcroMed Corp., in receiving FDA approval of the devices. The screws had been twice rejected by the FDA for use in the pedicle bones of the spine, but were split into two component parts and renamed “bone plates” and “bone screws.” Each was then approved under 510(k) for use in the long bones of the arms and legs as devices substantially equivalent to predicate devices already used in bone surgery. According to plaintiffs, this was done to defraud the FDA, since the intended use of the screws all along was as pedicle bone screws. The bone screws were subsequently implanted into the pedicles of numerous patients' spines, an off-label use. Some of those patients later turned into plaintiffs who claimed that Buckman and AcroMed had misled the FDA to gain approval for the device and had thus committed fraud upon the FDA.

The Supreme Court held that plaintiffs' claims were impliedly preempted by the FDCA and MDA. State law claims alleging fraud on the FDA were irreconcilably in conflict with the approval and enforcement schemes established by Congress in the FDCA. The FDCA gave the FDA ample authority to deter and punish fraud, and allowing state-law claims would upset the “somewhat delicate balance of statutory objectives.”

The Court went on to note that allowing “fraud-on-the-FDA claims could cause the agency's reporting requirements to deter off-label use … even though off-label use is generally accepted.” The “speedy ' 510(k) process could encounter delays, which would in turn impede competition among predicate devices and delay health care professionals' ability to prescribe appropriate off-label uses.”

Of particular importance, the Court drew a distinction between Buckman and Medtronic: “Medtronic claims arose from the manufacturer's alleged failure to use reasonable care in the production of the product, not solely from the violation of FDCA requirements … In the present case, however, the fraud claims exist solely by virtue of the FDCA disclosure requirements.”

This would seem to preclude tort liability stemming from off-label use of a drug. The FDA, with the Department of Justice, has ample authority to deter and punish improper off-label promotion, whereas civil liability under tort theory for off-label promotion to physicians would “deter off-label use” and “delay health care professionals' ability to prescribe appropriate off-label uses.” Moreover, such claims exist solely by virtue of the FDCA labeling requirements.

This is not to suggest that pharmaceutical companies engaging in false or misleading advertising should not be subject to civil liability to consumers, but state action under consumer protection law is a different matter from tort liability for allegations that drug manufacturers disseminated journal articles or hosted continuing medical education courses that included discussions of off-label uses already implemented by the medical community.

In this regard, the current crowd of Oxycontin' cases may be instructive. In those cases, plaintiffs allege that, apart from any labeling required by the FDCA, manufacturers have promoted the use of Oxycontin' for “off-label uses and doses which defendants knew or should have known would reasonably harm plaintiffs and others similarly situated.” McCallister v. Purdue Pharma L.P., 164 F. Supp.2d 783, 791 (S.D. W. Va. 2001). Still, courts have been slow to recognize any implication of Buckman beyond fraud on the FDA, and it is easy enough for a plaintiff to allege that he or she, rather than a federal agency, was defrauded. See Globetti v. Sandoz Pharmaceutical Corp., 2001 WL 419160 (N.D. Ala.) (“Notwithstanding that information may have been misrepresented to or concealed from the FDA, once defendant undertook to misrepresent those facts to plaintiff, or to conceal from plaintiff facts it was bound to disclose, the plaintiff's claim no longer rests simply on the assertion that the agency was defrauded but on the additional fact that she was defrauded.”)

The FDAMA

Congress recognized the importance of discourse between pharmaceutical companies and doctors regarding off-label use in the Food and Drug Administration Modernization Act of 1997 (FDAMA) when it carved out exceptions for pharmaceutical companies to distribute “written information concerning the safety, effectiveness, or benefit of a use not described in the approved labeling of a drug” under certain circumstances. 21 U.S.C. ' 360aaa et seq. The requirements state that: 1) the manufacturer must submit a new drug application for the off-label use; 2) the information cannot be abridged, false, misleading, or pose a significant health risk; 3) disseminated clinical research cannot be conducted by another manufacturer; 4) a copy of the disseminated materials must be submitted to the FDA; and 5) disclaimers must be prominently displayed with the materials. The FDAMA expressly prohibits manufacturers' dissemination of off-label information that does not comply with these regulations. 21 U.S.C. ' 331(z). Passage of the FDAMA probably strengthens the Buckman argument for preemption, since it further circumscribes the communications permissible by manufacturers.

The First Amendment

Before the FDAMA was passed, the FDA circulated three Guidance Documents describing its enforcement policy as it foresaw it under the new law. Washington Legal Foundation, which represented doctors, sued, claiming that the policies in the Guidance Documents violated its members' First Amendment right to receive off-label information from drug manufacturers.

The district court determined that the off-label communication contemplated by the Guidance documents was commercial speech and therefore entitled to limited First Amendment protection, then applied the Central Hudson test to determine whether the Guidance Documents unconstitutionally restricted commercial speech. Central Hudson Gas & Elec. Corp. v. Public Serv. Comm'n, 447 U.S. 557 (1980). Central Hudson presents a simple two-part test: a court first determines whether the speech at issue is false or inherently misleading. If the speech is truthful and not misleading, the government must demonstrate a substantial interest that is directly advanced by the regulation without burdening substantially more speech than necessary. While the court found that the Guidance Documents advanced the government's substantial interest in encouraging drug manufacturers to seek FDA approval for off-label uses, it also found that the policies were more restrictive than necessary to accomplish this goal. Thus, the government was in violation of drug manufacturers' First Amendment right to freedom of speech. The court enjoined the FDA from prohibiting manufacturers' dissemination of “enduring materials,” regardless of whether the materials had an exclusive or significant focus on off-label uses for prescription drugs.

Shortly after this injunction issued, the FDAMA became law, superceding the enjoined Guidances. The district court then ruled that its decision applied to the policies, not the documents, and the FDA appealed.

Then a funny thing happened. Both sides realized that their hard-fought lawsuit was a bit premature and a tad enigmatic. The FDA argued on appeal that the new law did nothing more than establish a “safe harbor” within which pharmaceutical manufacturers could disseminate information. Under the FDCA as enforced by the FDA for decades, off-label promotion was strictly proscribed. The FDAMA eased but did not curtail that policy: It was an expansion of manufacturers' rights to disseminate information. Moreover, the FDA argued that the FDAMA conferred to the agency no authority to restrict or sanction speech. The authority to declare a prescription drug “misbranded” is wholly contained within the FDCA. Confronted with this position, Washington Legal Foundation withdrew its constitutional objection to the FDAMA (though it paradoxically argued that the Court of Appeals should nonetheless affirm the lower court decision in case the challenged conduct, which had been enjoined before it became law, were ever to resume).

The Court of Appeals for the District of Columbia Circuit declined Washington Legal Foundation's invitation to affirm the district court decision and vacated the case and injunction. In its decision however, it noted that it did not reach the merits of the case and therefore did not criticize the reasoning or conclusions of the lower court. Moreover, it noted that a manufacturer could still argue that the FDA's use of the manufacturer's promotional materials regarding off-label uses as evidence in a particular enforcement action violated the First Amendment.

The Paradox

Drug manufacturers may only be able to either have their cake or eat it. If Buckman preempts tort liability for information disseminated by manufacturers, it is due to the regulatory framework designed by Congress to enforce liberally defined labeling and advertising requirements. If, on the other hand, information about off-label uses disseminated by manufacturers is constitutionally protected free speech that may be regulated no more than necessary to satisfy the government's substantial interest in encouraging drug manufacturers to seek FDA approval for off-label uses, manufacturers probably assume the risks of open communication along with the rewards.

There is a somewhat uncomfortable medium. If the government's substantial interest in encouraging drug manufacturers to seek FDA approval for off-label uses is only satisfied with stringent regulation, off-label promotion may be constitutionally protected free speech with federal preemption. Moreover, federal regulation may nonetheless conflict with state-law tort remedies. Since, in any case, these sorts of tort claims exist only in the context of labeling requirements, maybe manufacturers can have their cake and eat it too.

Is it ever appropriate for a drug manufacturer to disseminate information about an off-label use of a drug? If so, when is it inappropriate? Is the dissemination of such information commercial speech protected by the First Amendment that cannot be proscribed by the FDA? Can manufacturers be held accountable for this speech by the FDA or in a products liability action?

In the wake of the preemption analysis of Buckman Co. v. Plaintiffs' Legal Committee , 531 U.S. 341 (2001), and the First Amendment analysis of Washington Legal Foundation v. Henney, 202 F.3d 331 (2000), the dissemination of information about off-label uses of prescription drugs and medical devices is enigmatic legal territory. In the eyes of many commentators, these cases address entirely different issues. The two fight for the same territory, however, and both confuse the already foggy legal backdrop against which drug manufacturers' communications with doctors take place.

The Off-Label World

The Food, Drug, and Cosmetic Act (FDCA) regards a drug “misbranded” if its label does not bear “adequate directions for use.” 21 U.S.C. ' 352(f). This means that the label of a drug must reveal “all conditions, purposes, or uses for which such drug is intended, including [those] suggested in its oral, written, printed or graphic advertising.” 21 C.F.R. ' 201.5(a). Since the FDA approves all labeling of prescription drugs, the use of a drug for any purpose other than those spelled out on its label (those for which it and its labeling were approved) is an “off-label” use and therefore prohibited.

The FDA does not, however, regulate physicians, who may legally prescribe drugs for off-label use. As a result, most sources agree, off-label use of drugs is widespread. According to a Government Accounting Office Study in 1991, 56% of cancer patients reported use of off-label prescriptions while 33% of all prescriptions in cancer treatment were off-label. A survey of AIDS patients ascertained that 81% had received at least one off-label medication, while 40% of all reported drug use by AIDS patients was off-label. Another survey revealed that nearly all pediatric patients receive off-label medications. Similarly, a majority of antidepressant usage was found to be off-label. In yet another survey, all dermatologists answered that they commonly wrote off-label prescriptions. Finally, a survey of pregnant women found that 23% had taken at least one drug off-label during their third trimester. Tabarrok, “Assessing the FDA via the Anomaly of Off-Label Drug Prescribing,” The Independent Review, v. V, n. 1, 25 (2000). As one commentator put it, “off-label use is legal, common, and necessary.” Beck & Azari, “FDA, Off-Label Use, and Informed Consent: Debunking Myths and Misconceptions,” 53 Food & Drug L. J. 71, 72 (1998).

So, although manufacturers are prohibited by the FDCA from promoting drugs for off-label use, physicians may prescribe drugs off-label as they please. If manufacturers breach the FDCA rule, they can be sanctioned with harsh civil and criminal penalties, including felony charges. 21 U.S.C. ' 333(a); 18 U.S.C. ' 3571. The burning issue is this: May manufacturers be held liable for violations under tort theories or is civil liability for injury preempted by the FDCA?

Preemption

The Buckman line of cases really begins more than a decade ago with Cipollone v. Liggett Group Inc. , 505 U.S. 504 (1992). In Cipollone, plaintiff filed suit against cigarette manufacturers under a number of theories, including strict liability, fraud, negligence and breach of express warranty. The manufacturers argued that two federal labeling statutes expressly preempted all the plaintiff's claims. The first of these statutes stated that “no statement relating to smoking and health shall be required” as long as cigarettes are labeled in accordance with the provisions of the statute. 15 U.S.C. ' 1334 (1965). The second superceded the first and stated that “no requirement or prohibition based on smoking and health shall be imposed under state law” to cigarettes labeled in accordance with the provisions of the statute. 15 U.S.C. ' 1334(b) (1970).

The U.S. Court of Appeals for the Third Circuit found both preemption provisions ambiguous but found a broad implied preemption encompassed by congressional intent. Cipollone v. Liggett Group Inc. , 789 F.2d 181, 188 (1986). The U.S. Supreme Court rejected this analysis, holding that an implied preemption analysis is unwarranted where a germane express preemption provision exists. It found that Congress had limited the law's express preemption to advertising and labeling, leaving most common-law tort claims viable.

Then, in Medtronic Inc. v. Lohr , 518 U.S. 470 (1996), the Court found that the express preemption statute in the 1976 Medical Device Amendments (MDA), 15 U.S.C. ' 360C, to the FDCA did not preempt state law claims against a manufacturer of a Class III medical device approved under 510(k) of the Food Drug and Cosmetic Act (21 U.S.C. 360(k)). The Medtronic pacemaker at issue had been approved under 510(k), a provision that accelerates the approval process for medical devices “substantially equivalent” to products already approved. 510(k) is therefore an exception to the rigorous pre-marketing approval (PMA) process whereby safety and efficacy must be categorically demonstrated. The preemption provision of the MDA stated that no state could impose requirements different from or in addition to those imposed by the FDCA “relate[d] to the safety or effectiveness of the device.” 15 U.S.C. ' 360k(a). Because FDA regulations leading to approval of the device under 510(k) focused on equivalence rather than on safety and efficacy, state law that established requirements for safety and effectiveness were not preempted. The Court did not analyze the Medtronic case under a theory of implied preemption, nor did the Court address the fate of Class III devices approved under the rigors of the PMA process.

In Buckman, the Court looked at bone screws in a product liability context. Buckman Company had assisted the bone screws' manufacturer, AcroMed Corp., in receiving FDA approval of the devices. The screws had been twice rejected by the FDA for use in the pedicle bones of the spine, but were split into two component parts and renamed “bone plates” and “bone screws.” Each was then approved under 510(k) for use in the long bones of the arms and legs as devices substantially equivalent to predicate devices already used in bone surgery. According to plaintiffs, this was done to defraud the FDA, since the intended use of the screws all along was as pedicle bone screws. The bone screws were subsequently implanted into the pedicles of numerous patients' spines, an off-label use. Some of those patients later turned into plaintiffs who claimed that Buckman and AcroMed had misled the FDA to gain approval for the device and had thus committed fraud upon the FDA.

The Supreme Court held that plaintiffs' claims were impliedly preempted by the FDCA and MDA. State law claims alleging fraud on the FDA were irreconcilably in conflict with the approval and enforcement schemes established by Congress in the FDCA. The FDCA gave the FDA ample authority to deter and punish fraud, and allowing state-law claims would upset the “somewhat delicate balance of statutory objectives.”

The Court went on to note that allowing “fraud-on-the-FDA claims could cause the agency's reporting requirements to deter off-label use … even though off-label use is generally accepted.” The “speedy ' 510(k) process could encounter delays, which would in turn impede competition among predicate devices and delay health care professionals' ability to prescribe appropriate off-label uses.”

Of particular importance, the Court drew a distinction between Buckman and Medtronic: “Medtronic claims arose from the manufacturer's alleged failure to use reasonable care in the production of the product, not solely from the violation of FDCA requirements … In the present case, however, the fraud claims exist solely by virtue of the FDCA disclosure requirements.”

This would seem to preclude tort liability stemming from off-label use of a drug. The FDA, with the Department of Justice, has ample authority to deter and punish improper off-label promotion, whereas civil liability under tort theory for off-label promotion to physicians would “deter off-label use” and “delay health care professionals' ability to prescribe appropriate off-label uses.” Moreover, such claims exist solely by virtue of the FDCA labeling requirements.

This is not to suggest that pharmaceutical companies engaging in false or misleading advertising should not be subject to civil liability to consumers, but state action under consumer protection law is a different matter from tort liability for allegations that drug manufacturers disseminated journal articles or hosted continuing medical education courses that included discussions of off-label uses already implemented by the medical community.

In this regard, the current crowd of Oxycontin' cases may be instructive. In those cases, plaintiffs allege that, apart from any labeling required by the FDCA, manufacturers have promoted the use of Oxycontin ' for “off-label uses and doses which defendants knew or should have known would reasonably harm plaintiffs and others similarly situated.” McCallister v. Purdue Pharma L.P. , 164 F. Supp.2d 783, 791 (S.D. W. Va. 2001). Still, courts have been slow to recognize any implication of Buckman beyond fraud on the FDA, and it is easy enough for a plaintiff to allege that he or she, rather than a federal agency, was defrauded. See Globetti v. Sandoz Pharmaceutical Corp., 2001 WL 419160 (N.D. Ala.) (“Notwithstanding that information may have been misrepresented to or concealed from the FDA, once defendant undertook to misrepresent those facts to plaintiff, or to conceal from plaintiff facts it was bound to disclose, the plaintiff's claim no longer rests simply on the assertion that the agency was defrauded but on the additional fact that she was defrauded.”)

The FDAMA

Congress recognized the importance of discourse between pharmaceutical companies and doctors regarding off-label use in the Food and Drug Administration Modernization Act of 1997 (FDAMA) when it carved out exceptions for pharmaceutical companies to distribute “written information concerning the safety, effectiveness, or benefit of a use not described in the approved labeling of a drug” under certain circumstances. 21 U.S.C. ' 360aaa et seq. The requirements state that: 1) the manufacturer must submit a new drug application for the off-label use; 2) the information cannot be abridged, false, misleading, or pose a significant health risk; 3) disseminated clinical research cannot be conducted by another manufacturer; 4) a copy of the disseminated materials must be submitted to the FDA; and 5) disclaimers must be prominently displayed with the materials. The FDAMA expressly prohibits manufacturers' dissemination of off-label information that does not comply with these regulations. 21 U.S.C. ' 331(z). Passage of the FDAMA probably strengthens the Buckman argument for preemption, since it further circumscribes the communications permissible by manufacturers.

The First Amendment

Before the FDAMA was passed, the FDA circulated three Guidance Documents describing its enforcement policy as it foresaw it under the new law. Washington Legal Foundation, which represented doctors, sued, claiming that the policies in the Guidance Documents violated its members' First Amendment right to receive off-label information from drug manufacturers.

The district court determined that the off-label communication contemplated by the Guidance documents was commercial speech and therefore entitled to limited First Amendment protection, then applied the Central Hudson test to determine whether the Guidance Documents unconstitutionally restricted commercial speech. Central Hudson Gas & Elec. Corp. v. Public Serv. Comm'n , 447 U.S. 557 (1980). Central Hudson presents a simple two-part test: a court first determines whether the speech at issue is false or inherently misleading. If the speech is truthful and not misleading, the government must demonstrate a substantial interest that is directly advanced by the regulation without burdening substantially more speech than necessary. While the court found that the Guidance Documents advanced the government's substantial interest in encouraging drug manufacturers to seek FDA approval for off-label uses, it also found that the policies were more restrictive than necessary to accomplish this goal. Thus, the government was in violation of drug manufacturers' First Amendment right to freedom of speech. The court enjoined the FDA from prohibiting manufacturers' dissemination of “enduring materials,” regardless of whether the materials had an exclusive or significant focus on off-label uses for prescription drugs.

Shortly after this injunction issued, the FDAMA became law, superceding the enjoined Guidances. The district court then ruled that its decision applied to the policies, not the documents, and the FDA appealed.

Then a funny thing happened. Both sides realized that their hard-fought lawsuit was a bit premature and a tad enigmatic. The FDA argued on appeal that the new law did nothing more than establish a “safe harbor” within which pharmaceutical manufacturers could disseminate information. Under the FDCA as enforced by the FDA for decades, off-label promotion was strictly proscribed. The FDAMA eased but did not curtail that policy: It was an expansion of manufacturers' rights to disseminate information. Moreover, the FDA argued that the FDAMA conferred to the agency no authority to restrict or sanction speech. The authority to declare a prescription drug “misbranded” is wholly contained within the FDCA. Confronted with this position, Washington Legal Foundation withdrew its constitutional objection to the FDAMA (though it paradoxically argued that the Court of Appeals should nonetheless affirm the lower court decision in case the challenged conduct, which had been enjoined before it became law, were ever to resume).

The Court of Appeals for the District of Columbia Circuit declined Washington Legal Foundation's invitation to affirm the district court decision and vacated the case and injunction. In its decision however, it noted that it did not reach the merits of the case and therefore did not criticize the reasoning or conclusions of the lower court. Moreover, it noted that a manufacturer could still argue that the FDA's use of the manufacturer's promotional materials regarding off-label uses as evidence in a particular enforcement action violated the First Amendment.

The Paradox

Drug manufacturers may only be able to either have their cake or eat it. If Buckman preempts tort liability for information disseminated by manufacturers, it is due to the regulatory framework designed by Congress to enforce liberally defined labeling and advertising requirements. If, on the other hand, information about off-label uses disseminated by manufacturers is constitutionally protected free speech that may be regulated no more than necessary to satisfy the government's substantial interest in encouraging drug manufacturers to seek FDA approval for off-label uses, manufacturers probably assume the risks of open communication along with the rewards.

There is a somewhat uncomfortable medium. If the government's substantial interest in encouraging drug manufacturers to seek FDA approval for off-label uses is only satisfied with stringent regulation, off-label promotion may be constitutionally protected free speech with federal preemption. Moreover, federal regulation may nonetheless conflict with state-law tort remedies. Since, in any case, these sorts of tort claims exist only in the context of labeling requirements, maybe manufacturers can have their cake and eat it too.