Off-Label Communications

Solicited vs. Unsolicited

The draft guidance provides guidelines for determining whether a request for off-label information is “solicited” or “unsolicited.” The FDA proposes to define “unsolicited requests” as those not prompted by the company in any way, but rather initiated by persons who are “completely independent” of the company. “Solicited requests” would be characterized as those “requests for off-label information that are prompted in any way by a manufacturer or its representatives.” The draft guidance goes on to say that solicited requests may be “considered evidence of a firm's intent that a drug or medical device be used for a use other than that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.” In the draft guidance, the FDA provides several examples of solicited requests, including tweets announcing the results of a study that an off-label use is safe and effective, and the use of websites allowing viewers to receive standard responses through pull-down menus on product information, including off-label use information.

Public vs. Non-Public Unsolicited Requests

The draft guidance also distinguishes between “non-public” unsolicited requests and “public” unsolicited requests for off-label information. Non-public unsolicited requests include communications with manufacturers in a direct, one-on-one forum, such as individual phone calls or e-mails. As the FDA has stated before, as early as 1997, responses to unsolicited requests for information should be non-promotional and scientific or medical in nature, generated by medical or scientific personnel who are independent from sales and marketing departments, responsive only to the question asked, and provided only to the person making the request. Moreover, the FDA expects companies to provide the following information in response to unsolicited requests:

• A copy of the FDA-required/approved labeling.
• A statement identifying the approved/cleared use(s).
• A statement that the information contains references to uses not approved/cleared by the FDA.
• All important safety/risk information.
• A complete list of references, including journal articles that may provide negative information about off-label uses.

The FDA also advises companies to maintain written records of the nature of the request and the name, address, and affiliation of the requestor, as well as the information provided and any follow-up questions and responses.

Public unsolicited requests for information about off-label use are requests made in a “public forum,” including company-controlled websites, third-party discussion boards, and social media forums, and are not directed only to a company. The FDA explains that it has two concerns with responding to public unsolicited requests for off-label information. First, the agency notes that a public response on a website or social media forum would provide off-label information to individuals who did not request such information and, therefore, may promote a product for the off-label use. Second, the FDA is concerned about the “enduring nature of detailed public online response to off-label questions because [the] information may become outdated (e.g., new risk information may become available).” Thus, the FDA recommends in the draft guidance that a company's public response to an unsolicited public request should not include any off-label information.

Instead, so long as a public request pertains to the company's specific product, the FDA proposes that companies state that the information requested is off-label and provide contact information for the company's medical/scientific representative to obtain specific information about the off-label use. If the individual making the request contacts the company's medical representative, the guidelines for responding are the same as those for responding to a non-public unsolicited request, described above. In the draft guidance, the FDA does not distinguish between requests from medical professionals and patients or other non-medical individuals. Nor does the FDA distinguish online public forums from public meetings and conferences where questions about off-label use are occasionally raised.

Potential Impact on Product Liability Claims

Despite the disclosure safeguards in the draft guidance against making misleading statements, drug, biologics, and medical device manufacturers could still be subject to product liability claims that they failed to warn of risks associated with an off-label use.

In most cases, under the Learned Intermediary Doctrine, pharmaceutical and medical device manufacturers have a duty to warn the physician, not the patient, of potential risks associated with a product. In the context of off-label use of a product, however, courts vary regarding whether the learned intermediary defense protects manufacturers from liability for off-label use based on failure-to-warn claims. For example, in Robak v. Abbott Laboratories, 797 F. Supp. 475 (D. Md. 1992), the court held that the manufacturer had no duty to warn of risks associated with an off-label use of its drug simply because the drug was not indicated for that use. Id. at 476. Thus, under Maryland law, when a physician, within the practice of medicine, prescribes a drug for a condition for which it is not indicated, the manufacturer is not responsible for the consequences on any product liability theory. Id.; Davenport v. Medtronic, Inc., 302 F. Supp. 2d 419 (E.D. Pa. 2004) (finding a manufacturer's knowledge of an off-label use does not automatically subject the manufacturer to liability for failure-to-warn ).

Under Ohio law, whether there is a reasonably foreseeable risk associated with a manufacturer's product, giving rise to a duty to warn, focuses on the state of knowledge at the time the product left the manufacturer's hands and at the time the product was used. Thus, in Krumpelbeck v. Breg, Inc., 759 F. Supp. 2d 958 (S.D. Ohio 2010), the court held that a manufacturer did not breach a duty to warn because the evidence indicated that, at the time of the plaintiff's surgery, the purported association between chondrolysis and anesthetic infusion in the shoulder joint was unknown to the manufacturer, and, in fact, to the entire medical scientific community. Id. at 975.

Other courts have held that when manufacturers have knowledge of an off-label use, the Learned Intermediary Doctrine does not apply. In Knipe v. SmithKline Beecham, 583 F. Supp. 2d 602 (E.D. Pa. 2008) (applying New Jersey law), the court held that the manufacturer had a duty to warn of the risks associated with known off-label uses as soon as reasonably feasible. Id. at 628. The court rejected the manufacturer's argument that it did not have a duty to warn of risks associated with off-label uses of a drug, finding that the manufacturer's knowledge of an off-label use rebutted any reliance on the learned intermediary defense. Id.

A California court also held that a manufacturer can be liable for failure-to-warn of risks of off-label use of its product if it substantially profited from that off-label use and, therefore, knew or should have known the drug was being used off-label and warned of those risks. Miles Laboratories, Inc. v. Superior Court, 133 Cal. App. 3d 587, 595 (Cal. App. 4th 1982). The Learned Intermediary Doctrine did not apply because the manufacturer failed to provide the physician with a description of those risks. This appears to be a minority view, but nevertheless may create a dilemma for manufacturers, in those jurisdictions following this view, who must also comply with the FDA's guidance on how and what a company may legitimately disseminate about off-label uses.

Even in those jurisdictions that require warnings regarding risks associated with an off-label use, a plaintiff still has the burden of proving proximate causation ' that a manufacturer's failure-to-warn caused the plaintiff's injuries. For example, a manufacturer's failure-to-warn cannot “cause” a plaintiff's injuries when the physician, based on his own independent judgment and without regard to any information that could have been provided by the manufacturer, knew of the risks and prescribed the drug (or used the medical device) anyway. See Alexander v. Smith & Nephew, 98 F. Supp. 2d 1310 (N.D. Okla. 2000); Minisan v. Danek Medical, Inc., 79 F. Supp. 2d 970, 978 (N.D. Ind. 1999). Thus, a plaintiff must not only show that a manufacturer's warning was inadequate, but that such inadequacy affected the physician's use of the product. Minisan, 79 F. Supp. 2d at 978-79.

Conclusion

While the FDA's draft guidance would permit companies to provide off-label information in response to public unsolicited requests (specifically in the virtual context), it does not appear to introduce any particular distinctions or reduce a plaintiff's burden of proof with respect to failure-to-warn claims against manufacturers. Nonetheless, as comments regarding the draft guidance and the Citizen Petition are submitted, additional issues and questions are likely to be raised that may be ultimately addressed by the courts.

Areta L. Kupchyk is a partner and Tracey B. Ehlers is an associate with Nixon Peabody.

While the FDA has had a long-standing policy of permitting drug, biologics, and medical device companies to respond to unsolicited requests for information about off-label use of their products, there has been significant discussion over what constitutes “unsolicited” in this context. On July 5, 2011, seven medical products companies filed a “citizen petition” with the FDA, asking for clarification of several issues, including: 1) responses to unsolicited requests; 2) the meaning of scientific exchange; 3) the appropriate interactions with formulary committees, payors, and similar entities; and 4) the dissemination of third-party clinical practice guidelines. Although the Citizen Petition is pending, on Dec. 23, 2011, the FDA issued a draft guidance that addresses the first issue in the Petition. In the draft guidance titled “Responding to Unsolicited Requests for Off-Label Information About Prescription Drugs and Medical Devices,” the FDA describes how drug, biologics, and medical device manufacturers should respond to unsolicited requests for off-label information, including ' for the first time ' communications via the Internet and social media. (“Draft Guidance” is the FDA's proposed approach to compliance with a legal or regulatory requirement. When finalized, the draft guidance will represent the FDA's current thinking on this topic. Neither a draft nor final guidance creates or confers any rights for or on any person and does not operate to bind the FDA or the public. A person can use an alternative approach if the approach satisfies the requirements of the applicable statutes and regulations.)

Overview of the Draft Guidance

Companies are prohibited from misbranding an FDA-approved product. Any false or misleading statement or action about a product will misbrand the product. Touting an approved product for an unapproved use is an off-label promotion that, in the FDA's view, can mislead a consumer by suggesting the off-label use is approved and/or the product is safe and effective for such use. At the same time, the FDA recognizes that the legitimate exchange of scientific information ' including information about off-label use ' between medical professionals is not prohibited. In determining whether there has been a legitimate exchange of scientific information about off-label use or an impermissible promotion of such use, the FDA considers the circumstances of the exchange. The FDA has stated that a company may provide information about off-label use when, among other things, a medical professional makes an unsolicited request for such information. The FDA now proposes how it would interpret the term “unsolicited.”

Solicited vs. Unsolicited

The draft guidance provides guidelines for determining whether a request for off-label information is “solicited” or “unsolicited.” The FDA proposes to define “unsolicited requests” as those not prompted by the company in any way, but rather initiated by persons who are “completely independent” of the company. “Solicited requests” would be characterized as those “requests for off-label information that are prompted in any way by a manufacturer or its representatives.” The draft guidance goes on to say that 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.” In the draft guidance, the FDA provides several examples of solicited requests, including tweets announcing the results of a study that an off-label use is safe and effective, and the use of websites allowing viewers to receive standard responses through pull-down menus on product information, including off-label use information.

Public vs. Non-Public Unsolicited Requests

The draft guidance also distinguishes between “non-public” unsolicited requests and “public” unsolicited requests for off-label information. Non-public unsolicited requests include communications with manufacturers in a direct, one-on-one forum, such as individual phone calls or e-mails. As the FDA has stated before, as early as 1997, responses to unsolicited requests for information should be non-promotional and scientific or medical in nature, generated by medical or scientific personnel who are independent from sales and marketing departments, responsive only to the question asked, and provided only to the person making the request. Moreover, the FDA expects companies to provide the following information in response to unsolicited requests:

• A copy of the FDA-required/approved labeling.
• A statement identifying the approved/cleared use(s).
• A statement that the information contains references to uses not approved/cleared by the FDA.
• All important safety/risk information.
• A complete list of references, including journal articles that may provide negative information about off-label uses.

The FDA also advises companies to maintain written records of the nature of the request and the name, address, and affiliation of the requestor, as well as the information provided and any follow-up questions and responses.

Public unsolicited requests for information about off-label use are requests made in a “public forum,” including company-controlled websites, third-party discussion boards, and social media forums, and are not directed only to a company. The FDA explains that it has two concerns with responding to public unsolicited requests for off-label information. First, the agency notes that a public response on a website or social media forum would provide off-label information to individuals who did not request such information and, therefore, may promote a product for the off-label use. Second, the FDA is concerned about the “enduring nature of detailed public online response to off-label questions because [the] information may become outdated (e.g., new risk information may become available).” Thus, the FDA recommends in the draft guidance that a company's public response to an unsolicited public request should not include any off-label information.

Instead, so long as a public request pertains to the company's specific product, the FDA proposes that companies state that the information requested is off-label and provide contact information for the company's medical/scientific representative to obtain specific information about the off-label use. If the individual making the request contacts the company's medical representative, the guidelines for responding are the same as those for responding to a non-public unsolicited request, described above. In the draft guidance, the FDA does not distinguish between requests from medical professionals and patients or other non-medical individuals. Nor does the FDA distinguish online public forums from public meetings and conferences where questions about off-label use are occasionally raised.

Potential Impact on Product Liability Claims

Despite the disclosure safeguards in the draft guidance against making misleading statements, drug, biologics, and medical device manufacturers could still be subject to product liability claims that they failed to warn of risks associated with an off-label use.

In most cases, under the Learned Intermediary Doctrine, pharmaceutical and medical device manufacturers have a duty to warn the physician, not the patient, of potential risks associated with a product. In the context of off-label use of a product, however, courts vary regarding whether the learned intermediary defense protects manufacturers from liability for off-label use based on failure-to-warn claims. For example, in Robak v. Abbott Laboratories , 797 F. Supp. 475 (D. Md. 1992), the court held that the manufacturer had no duty to warn of risks associated with an off-label use of its drug simply because the drug was not indicated for that use. Id. at 476. Thus, under Maryland law, when a physician, within the practice of medicine, prescribes a drug for a condition for which it is not indicated, the manufacturer is not responsible for the consequences on any product liability theory. Id .; Davenport v. Medtronic, Inc. , 302 F. Supp. 2d 419 (E.D. Pa. 2004) (finding a manufacturer's knowledge of an off-label use does not automatically subject the manufacturer to liability for failure-to-warn ).

Under Ohio law, whether there is a reasonably foreseeable risk associated with a manufacturer's product, giving rise to a duty to warn, focuses on the state of knowledge at the time the product left the manufacturer's hands and at the time the product was used. Thus, in Krumpelbeck v. Breg, Inc. , 759 F. Supp. 2d 958 (S.D. Ohio 2010), the court held that a manufacturer did not breach a duty to warn because the evidence indicated that, at the time of the plaintiff's surgery, the purported association between chondrolysis and anesthetic infusion in the shoulder joint was unknown to the manufacturer, and, in fact, to the entire medical scientific community. Id. at 975.

Other courts have held that when manufacturers have knowledge of an off-label use, the Learned Intermediary Doctrine does not apply. In Knipe v. SmithKline Beecham , 583 F. Supp. 2d 602 (E.D. Pa. 2008) (applying New Jersey law), the court held that the manufacturer had a duty to warn of the risks associated with known off-label uses as soon as reasonably feasible. Id. at 628. The court rejected the manufacturer's argument that it did not have a duty to warn of risks associated with off-label uses of a drug, finding that the manufacturer's knowledge of an off-label use rebutted any reliance on the learned intermediary defense. Id.

A California court also held that a manufacturer can be liable for failure-to-warn of risks of off-label use of its product if it substantially profited from that off-label use and, therefore, knew or should have known the drug was being used off-label and warned of those risks. Miles Laboratories, Inc. v. Superior Court , 133 Cal. App. 3d 587, 595 (Cal. App. 4th 1982). The Learned Intermediary Doctrine did not apply because the manufacturer failed to provide the physician with a description of those risks. This appears to be a minority view, but nevertheless may create a dilemma for manufacturers, in those jurisdictions following this view, who must also comply with the FDA's guidance on how and what a company may legitimately disseminate about off-label uses.

Even in those jurisdictions that require warnings regarding risks associated with an off-label use, a plaintiff still has the burden of proving proximate causation ' that a manufacturer's failure-to-warn caused the plaintiff's injuries. For example, a manufacturer's failure-to-warn cannot “cause” a plaintiff's injuries when the physician, based on his own independent judgment and without regard to any information that could have been provided by the manufacturer, knew of the risks and prescribed the drug (or used the medical device) anyway. See Alexander v. Smith & Nephew , 98 F. Supp. 2d 1310 (N.D. Okla. 2000); Minisan v. Danek Medical, Inc. , 79 F. Supp. 2d 970, 978 (N.D. Ind. 1999). Thus, a plaintiff must not only show that a manufacturer's warning was inadequate, but that such inadequacy affected the physician's use of the product. Minisan, 79 F. Supp. 2d at 978-79.

Conclusion

While the FDA's draft guidance would permit companies to provide off-label information in response to public unsolicited requests (specifically in the virtual context), it does not appear to introduce any particular distinctions or reduce a plaintiff's burden of proof with respect to failure-to-warn claims against manufacturers. Nonetheless, as comments regarding the draft guidance and the Citizen Petition are submitted, additional issues and questions are likely to be raised that may be ultimately addressed by the courts.

Areta L. Kupchyk is a partner and Tracey B. Ehlers is an associate with Nixon Peabody.