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The Past, Present, and Future of Government Regulation of Off-Label Communications – Part 2

In my last post, I introduced a series of posts that will explore FDA’s historical approach to off-label drug and device communications, how that position has evolved (or not) to the modern day, and predict where that policy might end up a few years from now. This post focuses on the history of FDA’s off-label communication and promotion policy, and while it is by no means a comprehensive history, I attempt to reveal some of the origins and early development of the Agency’s approach to off-label uses and promotion.  In fact, FDA’s early position on off-label communications closely resembles the Agency’s stance on the subject today.

The Basis of the Off-Label Communications Prohibition: The Statute

As with most issues related to FDA, the basic origins of the Agency’s off-label promotion policy trace back to the Food, Drug, and Cosmetic Act (“FDCA”). Although there is no explicit language in the FDCA granting FDA the power to prohibit off-label activities, the primary authority to regulate communications about unapproved uses derives from the following sections of the FDCA as enacted in the U.S. Code:

  • 21 U.S.C. § 331(a) – Prohibiting the introduction of regulated products that are adulterated or misbranded into interstate commerce.
  • 21 U.S.C. § 331(k) – Prohibiting any act with respect to a regulated product after shipment in interstate commerce that results in the product being adulterated or misbranded.
  • 21 U.S.C. § 352(f)(1) – Deeming a drug or device misbranded if the labeling does not bear adequate directions for its intended use.
  • And to a lesser extent, 21 U.S.C. § 352(a) – Deeming a drug or device misbranded if the labeling is false or misleading.

These statutory sections have been in force since the FDCA was first enacted in 1938 and are common references throughout the history of FDA’s regulation of off-label communication. Not surprisingly, FDA cites these very sections as the basis for its authority in the memo discussing the Agency’s current position on off-label uses and communications.

Early Regulations Related to Off-Label Communications

Much of the analysis for identifying off-label communications rests on a regulated product’s intended use. Although many of the permissions and prohibitions described in the FDCA are based on intended use, FDA did not actually seek to define the phrase until 1952, when Title 21 of the CFR was amended with Section 1.106(o) (17 Fed. Reg. 6818, 6820).  While the regulation did explain the meaning of intended use, it also added the following warning to industry: “But if a manufacturer knows or has knowledge of facts that would give him notice, that a drug or device introduced into interstate commerce by him 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 which accords with such other uses to which the article is to be put.”  The language of 21 C.F.R. 1.106(o) should look familiar to anyone today because the same language is codified in 21 C.F.R. §§ 201.128 and 801.4, and in the language FDA attempted to change in a final rule released in January.

FDA built off of this intended use concept in developing proposed regulations governing off-label uses and communications. In 1972, faced with “widespread use of certain prescription drugs for conditions not named in the official labeling,” the Agency stated:

Section 1.106 of the regulations requires the labeling to contain appropriate information with respect to all intended uses of the drugs. Thus, where a manufacturer or his representative, or any person in the chain of distribution, does anything that directly or indirectly suggests to the physician or to the patient that an approved drug may properly be used for unapproved uses for which it is neither labeled nor advertised, that action constitutes a direct violation of the [FDCA] and is punishable accordingly. (37 Fed. Reg. 16,503, 16,504)

Based on this reasoning, FDA proposed, in part, the following regulations:

  • 21 C.F.R. § 130.___(a)(2) – “A prescription new drug may not be shipped in interstate commerce when intended for uses not contained in the currently approved labeling. Such unapproved uses may include, inter alia, a different dosage, or a different patient population, or a different regimen, than that approved. Section 505 of the [FDCA] requires that a manufacturer, physician, or other person who ships or requests shipment of a prescription new drug in interstate commerce, with the intent, or for the purpose, of an unapproved use must first file with [FDA] an investigational new drug plan . . . .”
  • 21 C.F.R. § 130.___(a)(3) – “Once a prescription new drug has been shipped in interstate commerce intended for its approved use(s) under approved labeling, the [FDCA] does not require a physician to file with [FDA] an investigational new drug plan in order to lawfully prescribe the drug for an unapproved use, when such prescribing is done as part of the practice of medicine.” (37 Fed. Reg. 16,503, 16,504-05)

The remaining sections state that when an off-label use may endanger patients or create a public health hazard, FDA has the authority to revise the labeling, obtain relevant data from the manufacturer, restrict distribution, or revoke the applicable NDA.

In this proposed regulation, FDA also drew a bright line distinction between advertising a drug for off-label uses as part of commercial activities and doctors prescribing or using a drug off-label in their professional judgment. FDA held that this distinction was faithful to the original intent behind the FDCA, stating:

Under the [FDCA], a drug approved for marketing may be labeled, promoted, and advertised by the manufacturer only for those uses for which the drug’s safety and effectiveness have been established and which FDA has approved. . . . The [FDCA] does not, however, limit the manner in which a physician may use an approved drug. (FDA Drug Bulletin, April 1982).

An Off-Label Policy Takes Hold

The proposed regulations were never finalized, but FDA continued to refer to them in future publications, stating “although no final rule has been issued on this subject, the agency has continued to apply the principles set forth in the preamble to the 1972 proposal” (48 Fed. Reg. 26,720, 26,733 (1983)). In a proposed rulemaking for a standard drug label format, FDA also cited the 1972 proposed rule and stated: “No clinical studies or references cited in [drug] labeling may refer to indications or uses not stated in the package insert. . . . The Commissioner concludes . . . that it is neither lawful nor in the interest of good patient care for the package insert to contain references to indications or usages for which substantial evidence of safety and effectiveness is not available” (40 Fed. Reg. 15,392, 15,393-94 (1975)).

Federal courts also appeared to support the Agency’s regulation of off-label communications according to this policy. In U.S. v. Evers, 643 F.2d 1043 (5th Cir. 1981), the Court of Appeals for the Fifth Circuit cited the 1972 proposed rule and stated that it was the basis of advice FDA gave to a physician about the off-label use of an approved drug.  Even before the proposed rule was published, the Court of Appeals for the Ninth Circuit held that a company had misbranded its product by publishing newspaper advertisements stating that the product could treat arthritis and rheumatism when such indications were not described on the product label (Alberty Food Products Co. v. U.S., 185 F.2d 321 (9th Cir. 1950)).

That’s all for the moment on the history behind FDA’s stance on off-label communications. Next time, I will discuss some prominent FDA Warning Letters, other enforcement actions, and guidance documents relating to off-label promotions.

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Benjamin advises pharmaceutical, medical device and biotech companies on the FDA regulatory process to identify the correct regulatory pathway, assisting with FDA communications and strategy.