FDA Enforcement Against Pharmaceutical Companies in the Product Promotion Arena

As of Nov. 22, 2010, the FDA's Division of Drug Marketing, Advertising, and Communications (DDMAC) had issued approximately 50 enforcement letters to prescription drug companies due to unlawful promotional activities. The number of letters has increased over the last few years, and it is noteworthy that some of these cases have led to scrutiny by other regulatory bodies, such as the U.S. Justice Department (DOJ) and state attorneys general, for potential violations of other laws, separate from the Federal Food, Drug, and Cosmetic Act. In general, because the FDA's Center for Devices and Radiological Health (CDRH) promotional review staff is much smaller, the number of CDRH enforcement letters in the promotional area has paled in comparison with those issued by DDMAC. However, recent activity indicates that CDRH is taking a more aggressive enforcement stance, in part, as its staff has increased modestly.

Warning Letters

In August 2010, CDRH issued a Warning Letter to a medical device company for the latter's improper promotion of its product. (Although these enforcement letters have been issued by the FDA and are a matter of public record, we have chosen not to identify the specific medical device manufacturers or device products, and, instead, focus on the substantive issues raised in each letter.) The letters are posted on the FDA's Web site. According to CDRH, a brochure listed on the company's Web site made certain claims that represented a major change or modification in the intended use for which the product was cleared for marketing. In this case, the FDA cleared the hip system device for numerous uses, but the company's promotion of the product for osseointegration went beyond the FDA-cleared uses. Therefore, the new intended use required a new pre-market notification, commonly referred to as a 510(k) submission. CDRH concluded that, because of the brochure claims, the product was “adulterated” (i.e., the company did not have an approved premarket approval application [PMA] or an approved application for investigational device exemption). The FDA also noted that the device was misbranded, because the company failed to submit a new 510(k). The company was told to cease marketing the device for unapproved uses immediately, and to take prompt corrective actions.

One month earlier, CDRH issued a Warning Letter to a company that improperly promoted unapproved uses. After a review of claims on the company's Web site, CDRH determined that the promotional claims suggested the “Patient Case System” was a medical device and, absent an approved a PMA or a cleared 510(k), the medical device product was adulterated and misbranded.

Earlier that month, CDRH issued a Warning Letter after it reviewed a White Paper and a product brochure on a medical device company's Web site. The FDA had cleared the medical device as “a cover for vessels following anterior vertebral surgery.”

The FDA had imposed the following limitation to appear in the Warnings section of the device's labeling and other promotional materials: “The safety and effectiveness of this device for reducing the incidence, severity and extent of post-operative adhesion formation have not been established.” The claims in the promotional materials were inconsistent with the required warning statement and represented a different intended use of the device. The FDA said in the Warning Letter:

We consider the ' claims to be outside the scope of your 510(k) clearance and in violation of the limitation described above. We consider these claims to be consistent with adhesion barrier claims because prevention of fibroblast penetration and facilitation of mobilization of necessary tissues, organs, and vessels are equivalent to adhesion barrier functions. Adhesions can form after a surgery, including through fibroblast proliferation, and when a subsequent surgery is needed, adhesions make it more difficult for medical professionals to access the surgical area. Thus, revision surgery poses a different risk profile than an initial surgery. Because fibroblast proliferation can result in adhesion formation, and a device that prevents fibroblast penetration would reduce the formation of adhesions at the surgical site, prevention of fibroblast penetration is equivalent to serving as an adhesion barrier. In addition, because mobilization of tissues, organs, and vessels during revision surgery can be hindered
by the presence of adhesions, a reduction in adhesions would facilitate the mobilization of these structures. Thus, facilitating mobilization of tissues, organs, and vessels also is equivalent to serving as an adhesion barrier. The above claims represent a different intended use of the device ' . Device marketed for an intended use as a cardiovascular adhesion barrier are considered class III devices requiring a premarket approval application (PMA).

As a result, [the product] as marketed for the new intended use is adulterated ' because you do not have an approved application for premarket approval (PMA) in effect ' or an approved application for an investigational device exemption (IDE) ' The device, as promoted for the new intended use, is also misbranded ' because you did not notify the agency of your intent to introduce the device into commercial distribution.

In June 2010, CDRH issued a Warning Letter to a device company marketing an infant-positioning mattress. The FDA took exception to the company Web site, which promoted the product for unapproved uses. The agency said:

A review of our records indicates that we cleared a premarket notification (510(k) for this device, with an indication “for healthy infants 0-9 months to aid in the prevention of skull deformities that can rise from consistent back-sleeping postures, namely the condition known as deformational (or positional) plagiocephaly.” We did not clear this device for use in the prevention of sudden infant death syndrome (SIDS) ' Promotion of this device for SIDS causes a significant change in the intended use of the device that requires the submission of a new 510(k).

During an inspection of a device company and review of its Web site, CDRH sent a Warning Letter in April 2010 due to unapproved promotional uses. Specifically the agency stated:

FDA cleared the [product] under premarket notification ' . FDA considers these claims on your website to be promotion of these devices for the treatment of atrial fibrillation. Although the box lesion and Maze lesions are ablation lesions performed on cardiac tissue during cardiac surgery, they are specifically intended to disrupt abnormal electrical conduction to isolate the pulmonary veins in an attempt to terminate a patient's atrial fibrillation. Therefore, FDA considers references to the classic box or Maze cardiac lesions to be synonymous with the treatment of atrial fibrillation. In addition, FDA reviewed your promotional materials collected during our inspection. Included in the launch kit materials intended to be distributed to the company representative were a product CD, a brochure, and a spec sheet. FDA considered these claims to be outside of the cleared intended use of your 510(k).

Lessons to be Learned

By issuing these enforcement letters, CDRH has demonstrated its intent to continue to investigate and take enforcement action against advertising and promotional materials that are violative of the FDC Act. A common theme in these letters has been where a company attempted to make specific claims with a general clearance from FDA, i.e., off-label uses. DDMAC has given the medical device industry a head start as to FDA's thinking is as it prosecutes unlawful promotional activity, and insight into the types of marketing statements which might raise governmental scrutiny. Specifically, off'label-use promotion that raises public health concerns is a more likely regulatory target because, by definition, these devices, promoted for unapproved uses, will lack adequate directions for use and warnings, as well as being potentially misleading. In addition, by reviewing both DDMAC and CDRH enforcement letters, one can see that the FDA will carefully review company or product Web sites, brochures, and other promotional items to evaluate how companies market their products.

Medical device companies should carefully review their internal procedures and promotional materials to ensure regulatory compliance and minimize potential liability. By remembering the past and not repeating others' mistakes, firms can try to avoid government condemnation.

Alan Minsk, a member of this newsletter's Board of Editors, is a Partner and Leader of the Food and Drug Practice Team of Arnall Golden Gregory LLP. E-mail: [email protected]. Phone: 404-873-8690.

In his “Reason in Common Sense, The Life of Reason (Vol. 1)”, George Santayana wrote: “Those who cannot remember the past are condemned to repeat it.”

We all can benefit from reviewing the lessons learned from past mistakes, whether committed by ourselves or others. The medical device industry would be well-served in heeding Santayana's warning; review of the Food and Drug Administration's enforcement in the pharmaceutical promotion area could offer insight into how it might minimize its regulatory risk. The device industry need only review recent FDA enforcement actions against its pharmaceutical brethren to understand better the types of governmental concerns. While the promotional rules might differ slightly for pharmaceutical and medical device firms, the basic rules apply equally.

Enforcement

As of Nov. 22, 2010, the FDA's Division of Drug Marketing, Advertising, and Communications (DDMAC) had issued approximately 50 enforcement letters to prescription drug companies due to unlawful promotional activities. The number of letters has increased over the last few years, and it is noteworthy that some of these cases have led to scrutiny by other regulatory bodies, such as the U.S. Justice Department (DOJ) and state attorneys general, for potential violations of other laws, separate from the Federal Food, Drug, and Cosmetic Act. In general, because the FDA's Center for Devices and Radiological Health (CDRH) promotional review staff is much smaller, the number of CDRH enforcement letters in the promotional area has paled in comparison with those issued by DDMAC. However, recent activity indicates that CDRH is taking a more aggressive enforcement stance, in part, as its staff has increased modestly.

Warning Letters

In August 2010, CDRH issued a Warning Letter to a medical device company for the latter's improper promotion of its product. (Although these enforcement letters have been issued by the FDA and are a matter of public record, we have chosen not to identify the specific medical device manufacturers or device products, and, instead, focus on the substantive issues raised in each letter.) The letters are posted on the FDA's Web site. According to CDRH, a brochure listed on the company's Web site made certain claims that represented a major change or modification in the intended use for which the product was cleared for marketing. In this case, the FDA cleared the hip system device for numerous uses, but the company's promotion of the product for osseointegration went beyond the FDA-cleared uses. Therefore, the new intended use required a new pre-market notification, commonly referred to as a 510(k) submission. CDRH concluded that, because of the brochure claims, the product was “adulterated” (i.e., the company did not have an approved premarket approval application [PMA] or an approved application for investigational device exemption). The FDA also noted that the device was misbranded, because the company failed to submit a new 510(k). The company was told to cease marketing the device for unapproved uses immediately, and to take prompt corrective actions.

One month earlier, CDRH issued a Warning Letter to a company that improperly promoted unapproved uses. After a review of claims on the company's Web site, CDRH determined that the promotional claims suggested the “Patient Case System” was a medical device and, absent an approved a PMA or a cleared 510(k), the medical device product was adulterated and misbranded.

Earlier that month, CDRH issued a Warning Letter after it reviewed a White Paper and a product brochure on a medical device company's Web site. The FDA had cleared the medical device as “a cover for vessels following anterior vertebral surgery.”

The FDA had imposed the following limitation to appear in the Warnings section of the device's labeling and other promotional materials: “The safety and effectiveness of this device for reducing the incidence, severity and extent of post-operative adhesion formation have not been established.” The claims in the promotional materials were inconsistent with the required warning statement and represented a different intended use of the device. The FDA said in the Warning Letter:

We consider the ' claims to be outside the scope of your 510(k) clearance and in violation of the limitation described above. We consider these claims to be consistent with adhesion barrier claims because prevention of fibroblast penetration and facilitation of mobilization of necessary tissues, organs, and vessels are equivalent to adhesion barrier functions. Adhesions can form after a surgery, including through fibroblast proliferation, and when a subsequent surgery is needed, adhesions make it more difficult for medical professionals to access the surgical area. Thus, revision surgery poses a different risk profile than an initial surgery. Because fibroblast proliferation can result in adhesion formation, and a device that prevents fibroblast penetration would reduce the formation of adhesions at the surgical site, prevention of fibroblast penetration is equivalent to serving as an adhesion barrier. In addition, because mobilization of tissues, organs, and vessels during revision surgery can be hindered
by the presence of adhesions, a reduction in adhesions would facilitate the mobilization of these structures. Thus, facilitating mobilization of tissues, organs, and vessels also is equivalent to serving as an adhesion barrier. The above claims represent a different intended use of the device ' . Device marketed for an intended use as a cardiovascular adhesion barrier are considered class III devices requiring a premarket approval application (PMA).

As a result, [the product] as marketed for the new intended use is adulterated ' because you do not have an approved application for premarket approval (PMA) in effect ' or an approved application for an investigational device exemption (IDE) ' The device, as promoted for the new intended use, is also misbranded ' because you did not notify the agency of your intent to introduce the device into commercial distribution.

In June 2010, CDRH issued a Warning Letter to a device company marketing an infant-positioning mattress. The FDA took exception to the company Web site, which promoted the product for unapproved uses. The agency said:

A review of our records indicates that we cleared a premarket notification (510(k) for this device, with an indication “for healthy infants 0-9 months to aid in the prevention of skull deformities that can rise from consistent back-sleeping postures, namely the condition known as deformational (or positional) plagiocephaly.” We did not clear this device for use in the prevention of sudden infant death syndrome (SIDS) ' Promotion of this device for SIDS causes a significant change in the intended use of the device that requires the submission of a new 510(k).

During an inspection of a device company and review of its Web site, CDRH sent a Warning Letter in April 2010 due to unapproved promotional uses. Specifically the agency stated:

FDA cleared the [product] under premarket notification ' . FDA considers these claims on your website to be promotion of these devices for the treatment of atrial fibrillation. Although the box lesion and Maze lesions are ablation lesions performed on cardiac tissue during cardiac surgery, they are specifically intended to disrupt abnormal electrical conduction to isolate the pulmonary veins in an attempt to terminate a patient's atrial fibrillation. Therefore, FDA considers references to the classic box or Maze cardiac lesions to be synonymous with the treatment of atrial fibrillation. In addition, FDA reviewed your promotional materials collected during our inspection. Included in the launch kit materials intended to be distributed to the company representative were a product CD, a brochure, and a spec sheet. FDA considered these claims to be outside of the cleared intended use of your 510(k).

Lessons to be Learned

By issuing these enforcement letters, CDRH has demonstrated its intent to continue to investigate and take enforcement action against advertising and promotional materials that are violative of the FDC Act. A common theme in these letters has been where a company attempted to make specific claims with a general clearance from FDA, i.e., off-label uses. DDMAC has given the medical device industry a head start as to FDA's thinking is as it prosecutes unlawful promotional activity, and insight into the types of marketing statements which might raise governmental scrutiny. Specifically, off'label-use promotion that raises public health concerns is a more likely regulatory target because, by definition, these devices, promoted for unapproved uses, will lack adequate directions for use and warnings, as well as being potentially misleading. In addition, by reviewing both DDMAC and CDRH enforcement letters, one can see that the FDA will carefully review company or product Web sites, brochures, and other promotional items to evaluate how companies market their products.

Medical device companies should carefully review their internal procedures and promotional materials to ensure regulatory compliance and minimize potential liability. By remembering the past and not repeating others' mistakes, firms can try to avoid government condemnation.

Alan Minsk, a member of this newsletter's Board of Editors, is a Partner and Leader of the Food and Drug Practice Team of Arnall Golden Gregory LLP. E-mail: [email protected]. Phone: 404-873-8690.