A Long Overdue Revision to the Intended Use Regulation

By Jeffrey K. Shapiro –

A determination of “intended use” is fundamental to FDA’s regulation of drugs and medical devices.  It is a primary basis for determining if an article is regulated by FDA at all, and if so, what regulatory requirements apply.

The intended use of an article for FDA regulatory purposes is not based upon the manufacturer’s subjective intent.  Rather, the determinant is “objective intent” based upon product labeling and advertising claims, i.e., the message about the recommended use of a drug or device that is communicated to the public.  E.g., Action on Smoking and Health v. Harris, 655 F.2d 236, 239 (D.C. Cir. 1980).

This regulatory framework is embodied in the parallel drug and device regulatory definitions of intended use (21 C.F.R. §§ 201.128 (drugs), 801.4 (devices)).  The definition provides:

The intent is determined by [a manufacturer’s] expressions or may be shown by the circumstances surrounding the distribution of the article.  This objective intent may, for example, be shown by labeling claims, advertising matter, or oral or written statements by [a manufacturer] or [its] representatives.

This approach allows drug and device manufacturers to influence the regulatory requirements applicable to their products based upon their own public statements.  But FDA has also claimed the authority to regulate based upon the actual uses of an article even if such uses are not claimed in labeling or advertising.  The agency gave itself this authority in another part of the same regulation as quoted above.  This sentence states:

But if a manufacturer knows, or has knowledge of facts that would give him notice, that a [drug or device] introduced into interstate commerce . . . is to be used for conditions, purposes, or uses other than the ones for which he offers it, he is required to provide adequate labeling for such a drug/device which accords with such other uses to which the article is to be put.

This “knowledge” provision for many years has hung like the Sword of Damocles over the heads of manufacturers who have any knowledge of off‑label uses of their products.  The possibility was always present that FDA could deem such knowledge to create a new intended use.  If so, a manufacturer could find itself in trouble for failing to provide adequate directions for this imputed intended use.  FDA also could deem the intended use an unapproved use outside the scope of the existing clearance or approval, opening the manufacturer up to criminal and civil liability for past sales and the burden of developing a new marketing application to bring the imputed use on‑label.

One effect of the “knowledge” sentence has been to inhibit manufacturers from presenting on‑label information to physicians whose prescribing or use of a drug or device is known to be off‑label.  Such interaction has been perceived to heighten the risk that FDA would deem the off‑label use to be the manufacturer’s intended use.

It is true that the “knowledge” sentence has been rarely enforced.  But it has remained on the books and available for FDA’s use.  In May 2010, for example, FDA cited it in a warning letter to DexCom, Inc.  FDA warned Dexcom that the firm “has knowledge . . . that your device . . . is being used for conditions, purposes, and uses other than ones for which it is offered.”  Therefore:  “Under 21 CFR 801.4 you are required to provide labeling for such a device which accords with such other uses.”  FDA stated that the off‑label uses “require action from you in accordance with this regulation.”

So it was welcome news last month that FDA published a proposed rule, 80 Fed. Reg. 57756 (Sept. 25, 2015), proposing to delete the “knowledge” sentence from the intended use regulations.  The preamble to the proposal states that FDA “would not regard a firm as intending an unapproved new use for an approved or cleared medical product based solely on the firm’s knowledge that such product was being prescribed or used by doctors for such use.”  Id. at 57,757.  (FDA cites for this proposition a brief it filed in a court case in January 2010 – five months before the Dexcom warning letter.)

The qualifier “solely” in the preamble statement just quoted could be read to imply that FDA will continue to consider such conduct if it occurs as part of a larger scheme of off‑label promotion.  It is difficult, however, to imagine how lawful conduct could be cited to enhance the unlawful nature of a particular promotional scheme.  Either FDA has evidence of off label promotion or it does not, and a manufacturer’s lawful dissemination of information should not (and likely would not) be permitted to enter into the equation in an enforcement action.

It is also remarkable that FDA provides almost no explanation for the proposed revision to the intended use regulations, considering that it is a fairly significant alteration to regulations that have been on the books for decades.  FDA says only that the revision to the intended use regulations is a “clarifying change,” 80 Fed. Reg. 57761, that will “conform them to how the Agency currently applies these regulations.”  Id. at 57756.

The agency’s unspoken motivation may be to reinforce the position it has taken in recent First Amendment litigation.  As noted above, the “knowledge” sentence has deterred manufacturers from presenting on‑label information in off-label settings.  That chilling effect was part of Par Pharmaceutical’s First Amendment challenge to FDA’s application of the intended use regulation.  We wrote about this aspect of the Par case here and here. 

FDA’s tactical response in the Par lawsuit was to assert that it would never bring an enforcement action solely based upon the presentation of on‑label information in an off‑label setting, so that Par had no legitimate fear of legal jeopardy.  Specifically, the government asserted that “nothing in § 201.128 suggests that disseminating information about a drug’s approved use in settings where the drug is prescribed off- label is sufficient, without more, to establish that the off label use is an intended one. And the government does not construe the regulation to establish any such rule.” The “knowledge” sentence, however, inconveniently undercuts this position, since it appears to provide FDA with legal authority that would support just such an enforcement action.  Although the Par case settled, FDA may be attempting to ward off future challenges by conforming its intended use regulations to its litigation position.

Bottom line: it will now be undisputedly lawful to disseminate on‑label information (e.g., cleared or approved labeling) and/or otherwise promote an on‑label use to physicians, regardless of whether they may prescribe or use the product off‑label.  The mere fact that a manufacturer’s representatives call on physicians knowing that such physicians will use the product off-label will no longer be sufficient, if it ever was, as a basis for FDA to conclude that the off-label use is intended by the manufacturer.  In the Par case, FDA took the position that that such activity would not be deemed to create a new intended use.  The proposed rule will make certain that the intended use regulations no longer support any other position.