United States

On Monday, December 3, 2012, the United States Court of Appeals for the Second Circuit issued a significant 2-1 opinion in the case of United States v. Caronia that may greatly affect a manufacturer's ability to promote off-label uses of its prescription drugs or medical devices. In reversing the criminal conviction of a sales representative of Jazz Pharmaceuticals for conspiracy to introduce a misbranded drug into interstate commerce, in violation of the U.S. Food Drug and Cosmetic Act ("FDCA"), the majority held that "the government cannot prosecute pharmaceutical manufacturers and their representatives under the [FDCA] for speech promoting the lawful, off-label use of an FDA-approved drug." Ultimately, the majority held that the criminal prosecution of a pharmaceutical salesman for merely promoting a scientifically supported safe off-label use of a prescription drug violated the right to free speech guaranteed by the First Amendment of the U.S. Constitution.

Although manufacturers of FDA-approved drugs and medical devices may be tempted by the Caronia decision to immediately send their sales representatives into doctors' offices and healthcare clinics to promote off-label uses of their products, such a reaction is likely not a prudent response. The Food and Drug Administration is undoubtedly not satisfied with this outcome and could seek en banc rehearing by the full panel of judges of the Second Circuit. It is also possible that the government will eventually file a petition in the U.S. Supreme Court, which may agree to hear this case given the significant First Amendment issues involved and the national implications on drug and medical device marketing and the related concerns for public health and safety. It is likely that the final chapter of the Caronia case has not been written and it is possible that the majority's decision could eventually be reversed. Moreover, the decision is notably limited in scope—applying only to criminal prosecutions for the sole act of promoting off-label uses of prescription drugs—and only applies in the three states within the Second Circuit (New York, Connecticut, and Vermont).

Perhaps most importantly, however, is that the decision does not preclude the government from considering off-label promotion as "evidence" of a manufacturer's intent to market a drug or medical device for unapproved purposes, which would still expose a manufacturer to serious penalties. Manufacturers of FDA-approved drugs and medical devices should therefore be well advised to continue abiding by the FDA's recommended guidelines with respect to promotion of off-label uses, at least until the Caronia case is final and it is known whether the FDA will change its rules. The rest of this Advisory discusses the FDA's current protocol for a manufacturer's promotion of off-label uses of its FDA-approved drugs or medical devices.

The FDA Generally Prohibits Promotion of Off-Label Uses By Manufacturers

As expressly stated by the FDA, "the Food Drug and Cosmetic Act and FDA's implementing regulations generally prohibit manufacturers of new drugs or medical devices from distributing products in interstate commerce for any intended use that FDA has not approved as safe and effective or cleared through a substantial equivalence determination."¹ Moreover, the FDCA prohibits "adulteration or misbranding" of drugs and medical devices,²and it is the FDA's position that "a medical device that is promoted for a use that has not been approved or cleared by FDA is adulterated and misbranded."³ Off-label promotion of drugs and medical devices by their manufacturers is thus not permitted and can result in significant penalties, including substantial fines and even criminal prosecution.

Nonetheless, the "FDA recognizes that these off-label uses or treatment regimens may be important therapeutic options and may even constitute a medically recognized standard of care."⁴ Acknowledging that physicians and other health care professionals may have legitimate and lawful reasons to know about the safety and efficacy of off-label uses of drugs and medical devices, the FDA has taken the position that drug and device manufacturers may transmit information about off-label uses of their products to physicians and health care professionals in narrowly and specifically defined ways. First, manufacturers may, under certain circumstances, distribute reprints of medical or scientific journal articles and reference publications discussing off-label uses of their drugs or devices. Second, manufacturers may respond to unsolicited inquiries about off-label uses of their drugs or devices. Each of these options is discussed in turn below.

Distribution of Medical or Scientific Journal Articles and Reference Publications

The FDA recognizes "the important public health and policy justification supporting dissemination of truthful and non-misleading medical journal articles and medical or scientific reference publications on unapproved uses of approved drugs and approved or cleared medical devices to healthcare professionals and healthcare entities."⁵ Therefore, the FDA permits drug and device manufacturers to distribute medical and scientific information concerning off-label uses of their products as long as the manufacturer abides by the following recommended guidelines.

First, any article that a manufacturer distributes should:

"be published by an organization that has an editorial board that uses experts who have demonstrated expertise in the subject of the article under review by the organization and who are independent of the organization to review and objectively select, reject, or provide comments about proposed articles; and that has a publicly stated policy, to which the organization adheres, of full disclosure of any conflict of interest or biases for all authors, contributors, or editors associated with the journal or organization;

be peer-reviewed and published in accordance with the peer-review procedures of the organization; and

not be in the form of a special supplement or publication that has been funded in whole or in part by one or more of the manufacturers of the product that is the subject of the article."⁶

On the other hand, distributed articles should not be:

"primarily distributed by a drug or device manufacturer, but should be generally available in bookstores or other independent distribution channels (e.g. subscription, Internet) where medical textbooks or periodicals are sold;

written, edited, excerpted, or published specifically for, or at the request of, a drug or device manufacturer; or

·edited or significantly influenced by a drug or device manufacturer or any individuals having a financial relationship with the manufacturer."⁷

Moreover, the information contained in any article distributed by a drug or medical device manufacturer should address reliable and significant non-clinical research or "adequate and well-controlled clinical investigations that are considered scientifically sound by experts with scientific training and experience to evaluate the safety and effectiveness of the drug or device."⁸ The information must not be "false or misleading . . . or pose a significant risk to public health, if relied upon."⁹ Examples of publications that the FDA would not consider proper for distribution include (i) letters to the editor; (ii) abstracts of a publication; (iii) reports of Phase 1 trials in healthy subjects; or (iv) reference publications that contain little or no substantive discussion of the relevant investigation or data.¹⁰

If a drug or medical device manufacturer desires to distribute medical or scientific information that meets the criteria discussed above, it should distribute such information in the following manner. The information should (i) be in the form of an unabridged reprint, copy of an article, or reference publication; (ii) not be marked, highlighted, summarized, or otherwise characterized by the manufacturer in any way; (iii) be accompanied by the approved labeling for the relevant drug or medical device; (iv) be accompanied, if one exists, by a comprehensive bibliography of publications discussing well-controlled clinical studies or reliable non-clinical research about the relevant off-label use; (v) be distributed along with a representative publication, if one exists, which reaches contrary or different conclusions about the relevant off-label use; and (vi) be distributed separate and apart from promotional information.¹¹ As an example of the last requirement, the FDA explains that "if a sales representative delivers a reprint to a physician in his office, the reprint should not be physically attached to any promotional material the sales representative uses or delivers during the office visit and should not be the subject of discussion between the sales representative and the physician during the sales visit."¹² Rather, the sales representative should refer any such question to the manufacturer's medical or scientific department, which should be separate from the sales and marketing departments.

Finally, any article or reference publication that a manufacturer distributes with respect to off-label uses "should be accompanied by a prominently displayed and permanently affixed statement disclosing:"

that the uses described in the article or publication have not been approved or cleared by FDA;

the manufacturer's interest in the related drug or medical device;

any author known to the manufacturer as having a financial interest in the drug or device or the manufacture, or who is receiving compensation from the manufacturer, along with the affiliation of the author, to the extent the manufacturer possesses such information, and the nature and amount of the author's financial interest, including any compensation received from the manufacturer;

any person who the manufacturer knows has provided funding for the study; and

all significant risks or safety concerns that the manufacturer is aware of concerning the off-label use which are not discussed in the distributed article or publication.¹³

Responding to Unsolicited Inquiries About Off-Label Uses

Additionally, a drug or medical device manufacturer may respond to a person or entity's unsolicited inquiry into off-label uses of its products and the FDA has provided guidance for how to properly respond.¹⁴ As the FDA has stated, drug and device manufacturers may respond to unsolicited inquiries with "responsive, nonpromotional, balanced scientific information, which may include information on unapproved uses, without subjecting their products to regulation based on the information."¹⁵ Such information may include scientific information maintained by the manufacturer's own scientific or medical departments.¹⁶

The key fact is that a request to which a manufacturer responds must be unsolicited. The FDA defines unsolicited requests as "those initiated by persons or entities that are completely independent of the relevant firm."¹⁷ Such unsolicited requests may include "both requests made directly and privately to firms and requests made in public forums, including through emerging electronic media."¹⁸ "A non-public unsolicited request is an unsolicited request that is directed privately to a firm using a one-one-one communication approach [such as an individual phone call or email]."¹⁹ On the other hand, "[a] public unsolicited request is an unsolicited request made in a public forum, whether directed to a firm specifically or to a forum at large [such as a question asked during a live presentation or one posted to an on-line public forum]."²⁰

Although a manufacturer may respond to unsolicited inquiries with truthful information about off-label uses in ways discussed below, it may not offer information about off-label uses in response to solicited requests. "FDA considers requests for off-label information that are prompted in any way by a manufacturer or its representatives to be solicited."²¹ The draft guidance document Responding to Unsolicited Requests provides a number of illustrative examples of solicited requests. For example, a request would be solicited if it was prompted by a manufacturer's sales representative mentioning an off-label use and inviting a physician or other health care professional to request more information. A request would also be solicited if it is prompted by a manufacturer's representative, such as a medical science liaison or paid speaker, presenting off-label information at a promotional event that is sponsored by the manufacturer. Drug and medical device manufacturers should avoid activities that may prompt a solicited request because "[s]uch solicited requests may be considered evidence of a firm's intent that a drug or medical device be used for a use other than that specifically approved or cleared by FDA."²²

Non-Public Unsolicited Requests

A manufacturer's response to a non-public unsolicited request for off-label information should comply with the following FDA guidelines:²³

The information should be distributed only to the person who made the request.

The information should answer only the specific question(s) asked. To that end, the manufacturer "should ensure that all pertinent background data are obtained to be able to determine what information is being requested before providing a response. If an unsolicited question is broad in nature, the firm should appropriately narrow the question."²⁴ Nonetheless, "if there is information about known or suspected risks associated with other diseases or conditions that is also relevant to the disease or condition for which information was requested, the firm should provide such information to ensure a complete and accurate presentation of the risk issues associated with the requested use."²⁵

The information should be truthful, not misleading, accurate and balanced.

Manufacturers should provide non-biased information and data, including that which may not support or cast doubt on the safety or efficacy of the particular off-label use.

Manufacturers should provide complete copies of any article or publication responsive to the request, not just summaries or abstracts.

Manufacturers may provide unpublished data that it has on file if such data is responsive to the request, although it should strive to "rely on published peer-reviewed journal articles, medical texts, or data derived from independent sources."²⁶
Manufacturers should only distribute information and data that is scientific in nature. The information should not be promotional in tone or presentation and should not be distributed with any promotional material.

Manufacturers' responses should come from its medical or scientific personnel and not from its sales or marketing personnel.

Manufacturers should include the following material with any information it distributes in response to an unsolicited request:²⁷

A copy of any FDA-required labeling.

"A prominent statement notifying the recipient that FDA has not approved or cleared the product as safe and effective for the use addressed in the materials provided."

"A prominent statement disclosing the indication(s) for which FDA has approved or cleared the product."

"A prominent statement providing all important safety information including, if applicable, any boxed warning for the product."

"A complete list of references for all of the information disseminated in the response."

Manufacturers should maintain the following records with respect to each non-public unsolicited request:

"The nature of the request for information, including the name, address, and affiliation of the requestor

Records regarding the information provided to the requestor

Any follow-up inquiries or questions from the requestor."²⁸

Public Unsolicited Requests

The FDA also offers guidance for responding to public unsolicited requests, such as those made at live presentations or posted on public on-line forums.²⁹ A drug or medical device manufacturer's response to a public unsolicited request should comply with the following FDA guidelines:

Manufacturers should only respond to requests that pertain specifically to its own product(s) and should not respond to requests related only to a competitor's product.

A manufacturer's public response should not contain any information about off-label uses. Instead, it should only provide specific contact information so that the person making the request can privately contact the manufacturer's medical or scientific personnel. If a subsequent private contact and request is then made, the manufacturer should comply with the guidelines discussed above.

A manufacturer's public response should also state that the question or request relates to an off-label use that is unapproved or uncleared by the FDA.

Any representative who provides a public response should disclose his or her involvement with the manufacturer.

Public responses should not be promotional in nature or tone.

Public responses should, to the extent possible, provide instructions for how to access current FDA-required labeling.

Conclusion

In order to avoid potential penalties for alleged unlawful promotion of off-label uses, drug and device manufacturers should limit their distribution of off-label information to the methods described in this Advisory. It is possible that the Caronia decision will eventually cause the FDA to reconsider its policies and change its rules, but until it does so, manufacturers who stray from the current policies risk facing serious penalties.

Footnotes

¹^{FDA Guidance Document,} ^{Good Reprint Practices for the Distribution of Medical
Journal Articles and Medical or Scientific Reference Publications
on Unapproved New Uses of Approved Drugs and Approved or Cleared
Medical Devices}^{, at p. 2 (January 2009)
(hereinafter, "}^{Good Reprint
Practices}^").

²^{21 U.S.C. § 331(b).}

³^{Good Reprint
Practices}^, ^supra ^{n.
1, at p. 2.}

⁴^{FDA Draft Guidance Document,} ^{Responding to Unsolicited Requests for Off-Label
Information About Prescription Drugs and Medical
Devices}^{, at p. 2 (December 2011) (hereinafter,
"}^{Responding to Unsolicited
Requests}^").

⁵^{Good Reprint
Practices}^, ^supra ^{n.
1, at pp. 2-3.}

⁶^Id. ^{at p. 3.}

⁷^Id.

⁸^Id. ^{at 4.}

⁹^Id.

¹⁰^Id.

¹¹^Id.

¹²^Id.^{"Similarly,
while reprints may be distributed at medical or scientific
conferences in settings appropriate for scientific exchange,
reprints should not be distributed in promotional exhibit halls or
during promotional speakers' programs."} ^Id.

¹³^Id. ^{at 5.}

¹⁴^{Responding to Unsolicited
Requests}^, ^supra ^n.
4.

¹⁵^{59 Fed. Reg. 59820, 59823
(November 18, 1994).}

¹⁶^{Responding to Unsolicited
Requests}^, ^supra ^{n.
4, at p. 2.}

¹⁷^Id. ^{at p. 4.}

¹⁸^Id. ^{at p. 3.}

¹⁹^Id. ^{at p. 4.}

²⁰^Id.

²¹^Id. ^{at p. 5}

²²^Id.

²³^See ^id. ^{at pp. 7-9 for the FDA's discussion of their guidelines as
well as illustrative examples.}

²⁴^Id. ^{at 7.}

²⁵^Id. ^{at 8.}

²⁶^Id.

²⁷^Id. ^{at p. 9.}

²⁸^Id.

²⁹^Id. ^{at pp. 10-12}

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Promoting Off-Label Uses Of Drugs And Medical Devices: Manufacturers Should Exercise Caution Despite Reversal Of Conspiracy Conviction In U.S. v. Caronia

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