Released by FDA: 4/6/00. Posted by FDA: 4/19/00
Jerome M. Prahl
Associate Director
Regulatory Affairs
G.D. Searle & Co.
4901 Searle Parkway
Skokie, Illinois 60077
RE: NDA 20-998 Celebrex (celecoxib) capsules
NDA 19-908 Anibien
(zolpidem tartrate) tablets
MACMIS ID #8518
Dear Mr. Prahi:
As part of its routine monitoring and surveillance program, the Division of Drug Marketing, Advertising, and Communications (DDMAC), has become aware of promotional materials for Celebrex (celecoxib) capsules and Ambien (zolpidem tartrate) tablets disseminated by G.D. Searle & Co. (Searle) in violation of the Federal Food, Drug, and Cosmetic Act (Act) and its implementing regulations. Reference is made to a “homemade” professional sales aid, disseminated by two Searle representatives in Virginia that was used to promote both Celebrex and Ambien. Our specific objections concerning the promotion of Celebrex and Ambien follow:
Celebrex (celecoxib) capsules
Misrepresentation of Safety Information
Promotional materials are false or misleading if they contain representations or suggestions that a drug is more effective, safer, or useful in a broader range of conditions and patients than has been demonstrated by substantial evidence. Your “homemade” professional sales aid presents claims that misrepresent the safety profile for Celebrex, including but not limited to:
 | You present the claim, “Celebrex can be used in Coumadin patients.”
This claim suggests that Coumadin, the brand name product for warfarin,
may be used in combination without risk. However, this claim
lacks important information regarding the risks that are known about
the use of Celebrex in combination with warfarin. Specifically,
the concurrent use of Celebrex and warfarin has caused bleeding events
in some patients, especially the elderly. In addition, this sales aid
fails to disclose the fact that anticoagulant activity should be
monitored, particularly in the first few days, after initiating or
changing CELEBREX therapy in patients receiving warfaiin or similar
agents, since these patients are at an increased risk of bleeding
complications. Your failure to disclose this important
information misrepresents the safety profile for Celebrex.
Consequently, the sales aid is misleading. |
| You present the claim, “Celebrex — Can be used in Aspirin Patients.” This claim suggests that Celebrex is safe to use in patients taking any dose of aspirin. However, this suggestion is misleading because there is a risk when using these drugs in combination. Specifically the Precaution sections of the approved product labeling (P1) states, “...concomitant administration of aspirin with CELEBREX may result in an increased rate of GI ulceration or other complications, compared to use of CELEBREX alone.” Therefore, failure to disclose this important risk information misrepresents the safety profile for Celebrex, and is thus, misleading. Furthermore, the suggestion that Celebrex may used in combination with any dose of aspirin is misleading because the P1 states, “Celebrex can be used with low dose aspirin” (emphasis added). |
Unsubstantiated Comparative Claims
Promotional materials are false or misleading if they contain a drug comparison that represents or suggests that a drug is safer or more effective than another drug when such has not been demonstrated by substantial evidence or substantial clinical experience. Some examples of misleading comparative claims in your “homemade” professional sales aid include:
| You present several unsubstantiated comparative claims, comparing
Celebrex to Relafen (nabumetone) that suggest that Celebrex is more
effective than Relafen, safer than Relafen, and has fewer side effects
than Relafen when such has not been demonstrated by substantial
evidence. Specifically, you present a side-by-side comparison of
selected information from the PIs of both of these products in your
sales aid. For example, your presentation that Relafen contains
“Standard NSAID labeling,” presented adjacent to the headline “Safety,”
misleadingly suggests that Celebrex is safer than Relafen because the
P1 for Celebrex does not contain standard NSAID class labeling where
the P1 for Relafen does. However, Celebrex’s P1 does contain
traditional NSAID class labeling. For instance, the
gastrointestinal (GI) warning common to all NSAIDs that states, “Serious
gastrointestinal toxicity such as bleeding, ulceration, and
perforation of the stomach, small intestine or large intestine, can
occur at any time, with or without warning symptoms, in patients
treated wth nonsteriodaj anti-inflammatory drugs (NSAIDs),” is
included in the P1 for Celebrex. Consequently, your suggestion that
Celebrex does not contain “Standard NSAID labeling” is misleading. |
| You also present several unsubstantiated comparative claims comparing Celebrex to Vioxx, including but not limited to, the claim that “Celebrex — can be used in Coumadin patients,” presented adjacent to the claim that Vioxx is “Contraindicated in Coumadin Patients.” These claims suggest that Celebrex may be used in a broader patient population, i.e., Coumadin patients, than Vioxx. However, this suggestion is false. In fact, the PIs for Celebrex and Vioxx both state that anticoagulant activity should be monitored when therapy with either Celebrex or Vioxx is initiated or changed, particularly in the first few days of therapy, in patients receiving warfarin or similar agents. |
Fair Balance
Promotional materials must present information relating to the contraindications, warnings, precautions, and side effects with a prominence and readability reasonably comparable to the presentation of information relating to the effectiveness of the product. The “homemade” professional sales aid is lacking in fair balance with respect to the content and presentation of risk information related to the use of Celebrex.
For example, although this piece contains numerous claims for the efficacy and safety of Celebrex, you have not presented any risk information concerning the contraindications, warnings, precautions, or side effects associated with Celebrex’s use (emphasis added).
Ambien (zolpidem tartrate) tablets
Misrepresentation of Efficacy information
| You selectively present only part of Ambien’s approved indication
throughout the “homemade” professional sales aid. For
example you present claims that Ambien is, “The ONLY proven Reliable
Choice for Insomnia,” and “Over 4 billion nights of insomnia
treatment worldwide.” These claims are misleading, because
this selective presentation of Ambien’s indication does not convey
the restrictions of Ambien’s use in the treatment of insomnia.
Specifically, you fail to disclose that Ambien is indicated for the
short-term treatment of insomnia. The indication section of the
P1 states, “Hypnotics should generally be limited to 7 to 10 days of
use, and reevaluation of the patient is recommended if they are to be
taken for more than 2 to 3 weeks.” |
| Additionally, you present claims that guarantee Ambien does not affect next-day mental performance. For instance, you state, “no next day residual effects, and “next-day functioning not compromised.” However, the P1 states, “In most instances memory problems can be avoided if you take Ambien only when you are able to get a full night’s sleep (7-8 hours) before you need to be active again” (emphasis added). Therefore, your guarantee that next-day mental performance will not be affected is misleading. In addition, these claims lack important qualifying information that is contained in the P1 for Ambien. Specifically, only when the patients are able to get between seven to eight hours of nighttime sleep are memory problems likely to be avoided. Consequently, these claims are also misleading, because this important qualifying information is not disclosed. |
Unsubstantiated Comparative Claims
| You present several unsubstantiated comparative claims for Ambien.
For example, you present the subheader that Ambien is “the ONLY
proven reliable choice for insomnia,” along with comparative claims,
including but not limited to, “fewer nighttime awakenings” and “more
total sleep time.” These statements make broad superiority
claims to all other sedative and hypnotic agents that are used for the
treatment of insomnia. However, these global superiority claims
have not been demonstrated by substantial evidence, and are therefore,
misleading. |
| Other unsubstantiated claims of Ambien superiority include a cost
comparison chart for Ambien and Sonata (zaleplon) capsules headed by
the question, “What is the COST for a night of ‘QUALITY’ sleep
or a ‘NAP’?” This presentation implies that only Ambien,
when compared to Sonata, can provide “quality sleep,” where as,
Sonata can only provide a “nap.” However, this implication
of Ambien’s superiority to Sonata has not been demonstrated by
substantial evidence. Therefore, these unsubstantiated
comparative claims of Ambien superiority are false or misleading. |
| You present several cost comparisons to not only Ambien and Sonata, but also between Celebrex and Relafen, and Celebrex and Vioxx. However, these comparisons are misleading because they imply that the drugs compared are equally safe, effective, and interchangeable. Furthermore, this cost information lacks substantiation and does not provide a reference as to the source of the cost information presented. |
Fair Balance
The “homemade” professional sales aid is also lacking in fair balance with respect to the content and presentation of risk information related to the use of Ambien. Although this piece contains numerous claims for the efficacy and safety of Ambien, you have not presented any risk information concerning the contraindications, warnings, precautions, or adverse events associated with Ambien’s use (emphasis added).
Failure to Submit
Promotional materials must be submitted to the FDA under Form FDA 2253 at the time of initial dissemination. However, our records indicate the “homemade” professional sales aid was not submitted at the time of initial use.
Conclusions and Requested Actions
Issues concerning “homemade” promotional pieces are not new issues relating to your promotion of Celebrex. On September10, 1999, we sent you a written inquiry concerning the extent of your involvement in the dissemination of two promotional pieces that were allegedly disseminated by Searle representatives. Both promotional pieces were entitled “Top 10 Reasons To Choose Celebrex Over the Other Branded COX 2 product,” and were lacking in fair balance, contained unsubstantiated comparative claims, and misrepresented Celebrex’s safety profile.
In your response, dated September 24, 1999, you confirmed that your representatives disseminated these “homemade” promotional materials, and characterized the activity as an isolated occurrence. Furthermore, you assured us that your company considers any distribution of “homemade” promotional materials to be a serious matter and that your “Guidelines for Employee Conduct” state that a representative will only use promotional materials that have been approved by the Searle Regulatory Approval Committee. Additionally, you stated that, “As a means of reinforcing this policy, our Vice President of Sales has sent a communication to each representative in the company describing the receipt of the DDMAC complaint letter, reminding them of our company policy, and cautioning them on the consequences of violating this policy.”
Notwithstanding these assurances, your representatives continue to engage in violative promotional practices. On December 1, 1999, we sent you a written inquiry about the alleged dissemination of the “homemade” professional sales aid that is the subject of this letter. On December 15, 1999, you responded that your representatives did indeed create and disseminate this professional sales aid and use it in the promotion of these two drug products.
We are concerned that the activities described above demonstrate a continuing pattern and practice of violative behaviors that evince widespread corporate involvement and acquiescence with your employees’ activities. Although we do not believe that we should interfere with, or comment on, a drug sponsor’s internal policies and procedures that are being instituted in response to serious violations of the law, it appears that your actions have not been successful in bringing your promotional practices into compliance with the law.
Consequently, we request that you provide a detailed response to this issue. In addition, you should immediately cease distribution of promotional materials for Celebrex and Ambien that contain the same or similar claims or presentations. You should submit a written response, on or before, April 20, 2000, describing your intent and plans to comply with the above. Your letter should also include a list of materials discontinued and the date on which these materials were discontinued.
If you have any questions or comments, please contact me by facsimile at (301) 594-6771, or by writing at the Food and Drug Administration, Division of Drug Marketing, Advertising and Communications, HFD-42, Rm. 17B-20, 5600 Fishers Lane, Rockville, MD 20857. We remind you that only written communications are considered official.
In all future correspondence regarding this matter, please refer to the MACMIS # 8518 and the NDA numbers.
Sincerely,
Spencer Salis, Pharm.D.
Regulatory Review Officer
Division of Drug Marketing,
Advertising and Communications
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