BANNING OFF-LABEL DRUG PROMOTION OFFENDS THE U.S. CONSTITUTION: MAKING THE STRONGEST CASE.

• Author: Noah, Lars

Commentators continue to debate whether the restrictions that the U.S. Food and Drug Administration (FDA) imposes on the dissemination of information about "off-label" uses of approved therapeutic products violate the First Amendment. (1) In previous work I have sided with those who question the constitutionality of these rules, (2) and lower federal courts have become increasingly receptive to the argument that commercial free speech principles enunciated by the U.S. Supreme Court may limit the government's ability to prevent pharmaceutical and medical device manufacturers from engaging in such communications. (3) Even so, one of the clearest illustrations of the unconstitutional operation of these restrictions has gone entirely unnoticed. This Essay explains why the application of restrictions on promoting off-label uses to bar generic drug manufacturers from touting uses newly approved by the FDA but only for their brand-name competitors cannot possibly pass muster under the First Amendment.

Since the mid-1970s, the U.S. Supreme Court has recognized that advertising enjoys some of the First Amendment's guarantees for freedom of expression, with its earliest decisions in this line all arising in the health care context. (4) Its newer decisions striking down laws for abridging commercial speech arose in that setting as well. (5) Although the Court has regularly applied a form of heightened scrutiny in such cases, the requirement that the government demonstrate it has narrowly tailored laws to serve a substantial interest has become more demanding over time. (6) Whenever officials seek to pursue collateral purposes such as dampening consumer demand, non-speech-restrictive alternatives (for example, barring the underlying conduct) invariably exist for accomplishing such goals. (7) As a consequence, this much has become abundantly clear: although it may protect consumers from false or misleading information, the government generally may not prohibit truthful and nondeceptive claims in pursuit of some other valuable ends. (8)

The FDA strictly controls what information may appear in the labeling of pharmaceutical products. (9) When it approves a new drug application (NDA), the agency specifies the allowable indications for use. (10) For some products, these statements are broad and general (for example, "temporary pain relief); for others, the approved uses may be incredibly narrow and specific (for example, for particular types of cancer with certain genetic mutations in patients who have failed to respond to other available chemotherapy agents). (11) Physicians generally need not, however, restrict their administration or prescribing of drugs based on FDA-approved labeling--they enjoy the freedom to engage in "off-label" use. (12) Knowing this, sponsors of new drugs may seek FDA approval for only a subset of possible indications, typically those that companies can most easily establish as safe and effective to the agency's satisfaction. (13) Once in the marketplace for one use, pharmaceutical manufacturers can often bank on widespread off-label use.

The brand-name manufacturer enjoys at least a five-year period of market exclusivity against generic competition. (14) After that time has elapsed (and any relevant patents expired), the FDA may approve an abbreviated new drug application (ANDA) so long as the sponsor of the generic version can establish its bioequivalence to the originally approved brand-name product. (15) The labeling for the generic must mimic the brand-name in almost all respects, (16) though additional uses subsequently approved for the brand-name drug initially may get carved out in the labeling for the generic. (17) Nowadays, generic drugs account for roughly ninety percent of all filled prescriptions. (18)

Under FDA regulations that go back more than half a century, manufacturers cannot share any information about off-label uses with doctors. (19) I happen to think that this blanket restriction runs afoul of the First Amendment, (20) but that view has made only limited inroads on the prevailing wisdom among commentators. (21) In part, the prohibition on off-label promotion treats indications not approved for labeling as unreliable unless and until the agency has had an opportunity to assess their validity. (22) A company first would have to file a supplemental new drug application (SNDA) and await approval from the FDA. (23) Although such "efficacy supplements" require far less effort than the original NDA, they are neither cheap nor fast (nor invariably successful). (24)

If approved, the SNDA would authorize the company to add a line or two to the list of indications in the package insert, which in turn would allow the company to advertise this now on-label use, (25) but in all other respects the product would remain identical to the one originally introduced. In an effort to encourage the filing of SNDAs, Congress decided to grant the SNDA sponsor (typically the brand-name manufacturer) three years of additional though partial exclusivity, (26) which means that competitors could not include any information about newly approved uses in the labeling or advertising for their otherwise identical products. (27) As a result, the seller of a generic drug cannot add the new indication to its labeling and also cannot advertise it as safe and effective for that use even though the FDA has approved precisely such a statement for brand-name product. (28) Physicians and pharmacists would, of course, remain free to prescribe or dispense the generic for off-label use. (29) After waiting for the three-year exclusivity period (and any method-of-use patents, (30) in case they run longer) to expire, and without having to submit any further evidence to the agency, competitors can seek permission to add this indication to the labeling for their generic drugs and then engage in advertising for this not-so-new use. (31)

In effect, the FDA initially grants the brand-name company a monopoly over information that it has anointed as truthful and nonmisleading. In no sense does the prohibition against labeling and advertising the new use for generic versions help to guard against the making of false or misleading claims. If agency approval of an SNDA allowed a competitor to revise the labeling for its previously approved generic drug immediately, then brand-name manufacturers would, of course, have even less of an already weak incentive to seek FDA approval of new uses. (32) The pursuit of such collateral purposes would not, however, stand much of a chance under the demanding form of heightened scrutiny currently used to assess restrictions on commercial speech. Indeed, it represents the flip-side of the problem confronted in Sorrell v. IMS Health Inc. (33) where the Supreme Court invalidated a state law designed to make it harder for brand-name drug companies to get the word out: the majority emphasized that the state had imposed a restriction on the creation and dissemination of information based on its content and speaker without adequate justification. (34)

Instead of granting three years of partial exclusivity, Congress could amend the statute to grant the NDA-holder two more years of full exclusivity with the first added use (and perhaps another year with a second added use). This would have the dual benefit of improving the incentive for filing SNDAs--without having to bar off-label promotion by the brand-name manufacturer--and ensuring that generic drug manufacturers do not encounter the prohibition on making off-label claims once the FDA approves their ANDAs. Congress crafted the six-month added exclusivity incentive for testing off-label uses in pediatric patients in roughly this manner. (35) Delaying generic entry might seem like a steep price for patients and their insurers to pay, (36) but the First Amendment casts serious doubt on the preferred current approach of casually trading away the speech rights of regulated entities. The issuance of "priority review vouchers," which entitle the holder to expedited processing of a future application for product approval, represents still another type of incentive that Congress has tried in this context. (37)

Why has this aspect of the problem gone entirely unnoticed? At present, and notwithstanding a desire to include new uses on the labeling for their products, generic drug manufacturers have little reason to advertise. (38) As with expenditures for research and development, they free-ride on the marketing efforts of brand-name manufacturers, counting on dramatically lower prices coupled with generic substitution policies to gain market share. (39) Nonetheless, if that business model changed for some reason, then generic sellers would confront an absolute barrier to communicating any information about new FDA-approved uses during the brand-name manufacturer's period of market exclusivity. For present purposes, this scenario has powerful explanatory value in highlighting...