Lynette Hopkinson
Associate Director, Regulatory Affairs
Eisai Corporation of North America
300 Tice Boulevard
Woodcliff Lake, New Jersey 07677

Dear Ms. Hopkinson:

The Division of Drug Marketing, Advertising, and Communications (DDMAC) of the U.S.  Food and Drug Administration (FDA) has reviewed a consumer-directed video for Gliadel® Wafer (polifeprosan 20 with carmustine implant) (Gliadel) titled “Gliadel Mechanism of Action Video” (mechanism of action video) submitted by Eisai Medical Research Inc.  (Eisai) under cover of Form FDA-2253 with the Consumer and Healthcare Provider Gliadel Website submission (GL135B) and found on the Gliadel website.¹  The promotional video minimizes the risks of the drug, overstates the efficacy of Gliadel, and makes unsubstantiated claims.  Thus, the promotional video misbrands the drug in violation of the Federal Food, Drug, and Cosmetic Act (the Act), 21 U.S.C. 352(a) & (n); 321(n).  See 21 CFR 202.1(e)(3)(i); (e)(5); (e)(6)(i), (vii); & (e)(7)(viii). 

Background

According to the Indications and Usage section of its PI, “GLIADEL® Wafer is indicated in newly-diagnosed high-grade malignant glioma patients as an adjunct to surgery and radiation.  GLIADEL® Wafer is indicated in recurrent glioblastoma multiforme patients as an adjunct to surgery.”

Gliadel is contraindicated in individuals who have demonstrated a previous hypersensitivity to carmustine or any of the components of the product.  Gliadel is associated with numerous warnings and precautions.  The PI contains warnings regarding complications of craniotomy, including seizures, intracranial infections, abnormal wound healing, and brain edema; along with cases of reported intracerebral mass effect that were unresponsive to corticosteroids.  Additionally the PI warns that Gliadel may cause a potential hazard to an unborn fetus. 

The PI includes precautions regarding avoiding communication between the surgical resection cavity and the ventricular system to prevent the wafers from migrating and causing obstructive hydrocephalus, as well as therapeutic interactions, carcinogenesis, mutagenesis, impairment of fertility, and for pregnancy, nursing mothers, and pediatric use. 

Gliadel is also associated with other risks, as described in the Adverse Reactions section of the PI including but not limited to: seizures; brain edema; healing abnormalities; and intracranial infection. 

Minimization and Omission of Risk Information

Promotional materials are misleading if they fail to present information about risks associated with a drug with a prominence and readability reasonably comparable to the presentation of information related to the effectiveness of the drug.  The promotional video minimizes the risks of Gliadel by failing to convey any of the serious risks of Gliadel during the audiovisual portion of the video.  Specifically, the first 4 minutes and 15 seconds of the promotional video are devoted to a description of primary brain tumors, the mechanism of action of Gliadel, and promotional statements about the benefits of Gliadel presented in a graphic and audio fashion.  In contrast, the presentation of serious risks associated with Gliadel is relegated to the end of the video following several cues suggesting the video has finished, where it is unlikely to draw the viewer’s attention.  These cues include the audio and visual elements fading out and a stagnant MGI Pharma logo being presented on screen with approximately 15 seconds of silence.  While the MGI logo is eventually followed by a running telescript with accompanying voiceover of the Indication, Contraindications, and Warnings associated with Gliadel, this presentation lacks comparable prominence to the benefit claims contained in the first 4 minutes and 15 seconds of the video.  The problems presented by this risk presentation are exacerbated by the fact that the video entirely omits any discussion of the precautions and adverse reactions associated with Gliadel. 

The overall effect of this presentation undermines the communication of important risk information, minimizing the risks associated with Gliadel and misleadingly suggesting that the drug is safer than has been demonstrated by substantial evidence or substantial clinical experience. 

Overstatement of Efficacy & Unsubstantiated Claims

Promotional materials are misleading if they represent or suggest that a drug is better or more effective than has been demonstrated by substantial evidence or substantial clinical experience.  The video contains the following misleading statements (emphasis added):

•  “Use of Gliadel wafer proloifeprosan 20 with carmustine implant can provide the benefits of locally delivered chemotherapy, which allows for up to 1000 times higher concentration of chemotherapy compared to IV administration, while attempting to avoid the serious systemic side effects.”

•  “At the molecular level the moisture between the cell membrane and Gliadel wafers breaks down the polymer, triggering a measured release of carmustine.”

•  “Animal studies have shown that released carmustine attaches to both residual cancer and non-malignant cells because of the constant rate breakdown of the polymer binding agent; the carmustine is released over a 7 to 10 day period.”

This first claim implies that Gliadel’s pharmacological properties have been shown to have a clinically significant effect by providing a chemotherapy dose 1000 times higher than systemic chemotherapy.  The second and third claims imply that the carmustine in Gliadel is released in a specific dose over a specific period of time.  We are not aware of substantial evidence or substantial clinical experience to support these claims.  Although there is evidence for the hydration induced breakdown of the polymer, we are unaware of studies substantiating the claimed tissue concentrations of carmustine surrounding the Gliadel implant over a specified amount of time.  According to the Clinical Pharmacology section of the Package Insert (emphasis added): “The absorption, distribution, metabolism, and excretion of the copolymer in humans is unknown.  Carmustine concentrations delivered by GLIADEL® Wafer in human brain tissue have not been determined.  Plasma levels of carmustine after GLIADEL® Wafer implant were not determined.”  If you do, in fact, have data to support these claims, you should submit them to the FDA for review. 

Conclusion and Requested Actions

For the reasons discussed above, the video misbrands Gliadel in violation of the Act, 21 U.S.C. 352(a) & (n); 321(n). See 21 CFR 202.1(e)(3)(i); (e)(5); (e)(6)(i), (vii); & (e)(7)(viii). 

DDMAC requests that Eisai immediately cease the dissemination of violative promotional materials for Gliadel such as those described above.  Please submit a written response to this letter on or before June 11, 2010, stating whether you intend to comply with this request, listing all promotional materials (with the 2253 submission date) for Gliadel that contain violations such as those described above, and explaining your plan for discontinuing use of such violative materials.  Please direct your response to me at the Food and Drug Administration, Center for Drug Evaluation and Research, Division of Drug Marketing, Advertising, and Communications, 5901-B Ammendale Road, Beltsville, MD 20705-1266, or facsimile at 301-847-8444.  In all future correspondence regarding this matter, please refer to MACMIS 18662 in addition to the NDA number.  We remind you that only written communications are considered official. 

The violations discussed in this letter do not necessarily constitute an exhaustive list.  It is your responsibility to ensure that your promotional materials for Gliadel comply with each applicable requirement of the Act and FDA implementing regulations. 

Sincerely,

Stephanie Victor, PharmD
Regulatory Review Officer
Division of Drug Marketing,
Advertising and Communications

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¹  http://www.gliadel.com/consumer/about/moa_video.aspx, last accessed May 26, 2010.