Michele Sharp, Pharm.D. D
irector, U.S. Regulatory Affairs
Eli Lilly and Company
Lilly Corporate Center
Indianapolis, Indiana 46285

RE:  NDA #22-148
       Cymbalta (duloxetine hydrochloride) Delayed-Release Capsules for Oral Use
       MACMIS #18149

Dear Dr. Sharp:

As part of its monitoring and surveillance program, the Division of Drug Marketing, Advertising, and Communications (DDMAC) of the U.S.  Food and Drug Administration (FDA) has reviewed a direct-to-consumer (DTC) print advertisement (“Print Ad”) (DD57640) and a WebMD Little Blue Book Rheumatology edition with fibro message (“Blue Book Message”) (DD53942) for Cymbalta (duloxetine hydrochloride) Delayed-Release Capsules for Oral Use (Cymbalta) submitted by Eli Lilly and Company (Lilly) under cover of Form FDA 2253.  The Print Ad is false or misleading in that it presents efficacy claims for Cymbalta, but fails to adequately communicate the risks associated with its use.  The Blue Book Message is false or misleading because it overstates the efficacy of Cymbalta and minimizes the risks associated with the drug.  Thus, the Print Ad and Blue Book Message misbrand Cymbalta in violation of the Federal Food, Drug, and Cosmetic Act (the Act), 21 U.S.C.  352(a) & (n), 321(n), and FDA implementing regulations.  See 21 CFR 202.1(e)(3)(i); (e)(6)(i); (e)(7)(i), (viii) & (ix). 

Background

The Indications and Usage section of the approved product labeling (PI) for Cymbalta states the following (in pertinent part):

Cymbalta is indicated for the management of fibromyalgia. 

Cymbalta is associated with numerous risks.  The PI contains a Boxed Warning regarding suicidality and antidepressant drugs as well as contraindications for concomitant use with a monoamine oxidase inhibitor (MAOI) and in patients with uncontrolled narrow-angle glaucoma.  The PI also contains numerous warnings and precautions, including hepatotoxicity, orthostatic hypotension and syncope, serotonin syndrome or neuroleptic malignant syndrome (NMS)-like reactions, abnormal bleeding, discontinuation of treatment with Cymbalta, effect on blood pressure, clinically important drug interactions, use in patients with concomitant illness, and urinary hesitation and retention.  The most common adverse reactions from pooled trials for all approved indications in Cymbalta-treated patients (incidence of at least 5% and at least twice the incidence in placebo patients) were nausea, dry mouth, constipation, somnolence, hyperhidrosis, and decreased appetite.  Additionally, the most common adverse reactions (occurring at an incidence of >10%) from the fibromyalgia trials were nausea, headache, dry mouth, insomnia, constipation, fatigue, diarrhea, decreased appetite, dizziness, and somnolence. 

Furthermore, figures 3 and 4 of the CLINICAL STUDIES section of the PI indicate that 46% and 37% of fibromyalgia patients who received 60 mg of Cymbalta once daily achieved a 30% improvement in pain from baseline in clinical studies 1 and 2 respectively. 

Print Ad

Omission of Risk Information

Promotional materials are misleading if they fail to reveal material facts in light of the representations made by the materials or with respect to consequences that may result from the use of the drug as recommended or suggested by the materials.  The Print Ad is misleading because it presents various efficacy claims for Cymbalta, but fails to communicate any risk information in the main part of the ad.  Specifically, the Print Ad prominently presents a picture of a woman curled up on a couch with the statement “FIBRO PAIN” (emphasis original) on her right knee along with various efficacy claims such as the following for Cymbalta that are presented in large, bolded and colorful text and graphics (this does not constitute a comprehensive list):

•  “Are you paying the price for Fibromyalgia pain? Cymbalta can help.”
•  “Fibromyalgia is painful.  Cymbalta can help.”
•  “Taking Cymbalta just once every day can reduce the level of fibromyalgia pain.  You may begin to function better and feel better.”

(emphasis original)

However, the main body of the Print Ad entirely omits risk information, including the contraindications, warnings and precautions, and the most frequently reported adverse reactions from the PI.  We note that the Print Ad contains the statement, “See left page for Important Safety Information, including Boxed Warning.” (emphasis original) at the bottom of the page and that risk information is presented on an adjacent page, but this is not sufficient to provide appropriate qualification or pertinent information for the claims made in the body of the ad or to mitigate the overall misleading presentation.  This risk information is placed in a single column in a single-spaced paragraph on a page with unrelated advertisements or magazine content.  It appears unconnected to the main body of the Print Ad and is not likely to draw readers’ attention.  For promotional materials to be truthful and non-misleading, they must contain risk information in each part as necessary to qualify any effectiveness or safety claims made in that part. 

Blue Book Message

Minimization of Risk Information

Promotional materials are misleading if they fail to present risks associated with a drug with a prominence and readability reasonably comparable with the presentation of information relating to the effectiveness of the drug.  The middle spread of the WebMD Little Blue Book Rheumatology edition presents a Cymbalta promotional piece with the claim, “53% More than half of patients with fibromyalgia treated with Cymbalta had a 30% improvement in pain severity at study endpoint” (emphasis original).  This efficacy claim is presented in very large bolded yellow font on a blue background with significant white space.  The risk information is presented on the preceding pages in black, smaller font size, in single-spaced paragraph format, and the header “Important Safety Information for Cymbalta® (duloxetine HCl)” is presented two pages before the efficacy claim (in the reverse order in which this information is typically presented), making it not visible to viewers looking at the efficacy spread.  This overall presentation misleadingly minimizes the serious risks associated with Cymbalta because it fails to convey this important risk information with a prominence and readability reasonably comparable to the efficacy claim. 

In addition, the back cover of the Blue Book Message contains a similar misleading presentation that minimizes the risks associated with Cymbalta.  The back cover presents the efficacy claim, “Presenting effective pain relief for your patients with fibromyalgia,” along with Cymbalta’s indication and a visual image of a Cymbalta 60 mg capsule, while the risk information is presented inside the back cover and on the preceding page.  Furthermore, the accompanying PI booklet is affixed to the inside back cover, thereby obscuring the immediately preceding page of risk information.  Additionally, the title of the PI, “Prescribing Drug Information for The WebMD Little Blue Book 2008 Edition RH-CYM,” gives no clear information as to the content of the PI or the risk information beneath the PI booklet.  The overall effect of this presentation undermines the communication of important risk information, minimizing the risks associated with Cymbalta and misleadingly suggesting that Cymbalta is safer than has been demonstrated. 

We note the statement, “See Important Safety Information, including Boxed Warning, on previous pages.  Please see accompanying booklet for full Prescribing Information.” (emphasis original) appears in small type, at the bottom of the pages that contain efficacy claims.  However, this does not mitigate the misleading minimization of risk information. 

Overstatement of Efficacy

Promotional materials are misleading if they suggest that a drug product is more effective than has been demonstrated by substantial evidence or substantial clinical experience.  The Blue Book Message states the following (emphasis original):

53%
More than half of patients with fibromyalgia treated with Cymbalta had a 30% improvement in pain severity at study endpoint. 

The Blue Book Message refers readers to Lilly’s website, www.insidecymbalta.com, which repeats the same claim.¹ These claims overstate the efficacy of Cymbalta by implying that over half of the fibromyalgia patients treated with Cymbalta will achieve a 30% improvement in pain.  We are not aware of substantial evidence or substantial clinical experience to support this claim.  Specifically, figures 3 and 4 in the CLINICAL STUDIES section of the PI indicate that 46% and 37% of fibromyalgia patients who received 60 mg of Cymbalta once daily achieved a 30% improvement in pain from baseline in the Cymbalta clinical studies 1 and 2 respectively.  The Blue Book Message references data-on-file to support this claim; this data was a pooled analysis of the results from the Cymbalta clinical studies 1 and 2 presented in the PI.  However, unlike the data presented in the PI, this data was reanalyzed using a last-observation-carried-forward (LOCF) imputation method.  An analysis of the clinical studies data for Cymbalta using an LOCF imputation method does not constitute substantial evidence or substantial clinical experience to support promotional claims.  As noted in the Summary Review of Regulatory Action for NDA 22-148 of June 13, 2008 (Section 7, page 4-5), it is a “well established policy of the Division (that Lilly has been aware for a number of years) that a drug product that is used primarily to treat pain is only considered to be effective if the side effects caused by that drug are tolerable and patients are able to remain on the drug.” In both fibromyalgia clinical studies for Cymbalta, almost 35% of treated subjects discontinued treatment prior to completion of the studies.  Approximately 40 to 60% of the dropouts were due to adverse events.  Thus, carrying forward a good score (using LOCF) for patients who dropped out is misleading, since dropping out for lack of efficacy or for toxicity is in itself a negative outcome.  These presentations therefore overstate the efficacy of Cymbalta. 

Conclusion and Requested Action

For the reasons discussed above, the Print Ad and Blue Book Message misbrand Cymbalta in violation of the Federal Food, Drug, and Cosmetic Act (Act), 21 U.S.C.  352(a) & (n), 321(n), and FDA implementing regulations.  See 21 CFR 202.1(e)(3)(i); (e)(6)(i); (e)(7)(i), (viii) & (ix). 

DDMAC requests that Lilly immediately cease the dissemination of violative promotional materials for Cymbalta, such as those described above.  Please submit a written response to this letter on or before January 22, 2010, stating whether you intend to comply with this request, listing all promotional materials (with the 2253 submission date) for Cymbalta 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, facsimile at 301-847-8444.  In all future correspondence regarding this matter, please refer to MACMIS # 18149 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 Cymbalta comply with each applicable requirement of the Act and FDA implementing regulations. 

Sincerely,

 

Twyla Thompson, Pharm.D.                         Mathilda Fienkeng, Pharm.D. 
Regulatory Review Officer                            Regulatory Review Officer
Division of Drug Marketing                           Division of Drug Marketing,

___________________________________________________________________

¹  http://www.insidecymbalta.com/productinformation/fibromyalgia/efficacy/significantpainimprovement.jsp