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Tercica

  

Department of Health and Human Services logoDepartment of Health and Human Services

Public Health Service
Food and Drug Administration
 Silver Spring, MD 20993
 

11/03/2010
 

TRANSMITTED BY FACSIMILE

Jean-Luc Bélingard
Chairman and CEO
Ipsen Group – Tercica Inc.
2000 Sierra Point Parkway, Suite 400
Brisbane, CA 94005

RE: NDA #021839
INCRELEX® (mecasermin [rDNA origin] injection)
MACMIS #18137
 

WARNING LETTER

Dear Mr. Bélingard:

The Division of Drug Marketing, Advertising, and Communications (DDMAC) has reviewed a letter signed by Ron G. Rosenfeld, M.D. (Letter) and the “Diagnostic and Therapeutic Considerations in Insulin-Like Growth Factor Deficiency White Paper and Growth Assessment Tools” (White Paper and Assessment Tools) for INCRELEX® (mecasermin [rDNA origin] injection) (Increlex) sponsored by Tercica, Inc. (a subsidiary of the Ipsen Group) (Ipsen), and submitted by Tercica under cover of Form FDA-2253 for Increlex. These promotional materials are false or misleading because the Letter, White Paper, and Assessment Tools omit important risk information, and the White Paper and Assessment Tools broaden the indication for Increlex. Therefore, these promotional materials misbrand Increlex in violation of the Federal Food, Drug, and Cosmetic Act (the Act), 21 U.S.C. 352(a) and 321(n). Cf. 21 CFR 202.1(e)(5)(i) & (iii) and (e)(6)(i). In addition, it appears that these promotional materials were not accompanied by the FDA-approved product labeling (PI) for Increlex in violation of 21 CFR 201.100(d). These violations are concerning from a public health perspective because they encourage the use of Increlex in circumstances other than those for which the drug has been shown to be safe and effective and omit important risk information for the drug.

Background

The INDICATIONS AND USAGE section of the FDA-approved product labeling (PI) for Increlex states:

INCRELEX® (mecasermin [rDNA origin] injection) is indicated for the long-term treatment of growth failure in children with severe primary IGF-1 [Insulin-like growth factor 1] deficiency (Primary IGFD) or with growth hormone (GH) gene deletion who have developed neutralizing antibodies to GH.

Severe Primary IGFD is defined by:

• height standard deviation score ≤ -3.0 and
• basal IGF-1 standard deviation score ≤ -3.0 and
• normal or elevated growth hormone (GH).

Severe Primary IGFD includes patients with mutations in the GH receptor (GHR), post-GHR signaling pathway, and IGF-1 gene defects; they are not GH deficient, and therefore, they cannot be expected to respond adequately to exogenous GH treatment.

INCRELEX® is not intended for use in subjects with secondary forms of IGF-1 deficiency, such as GH deficiency, malnutrition, hypothyroidism, or chronic treatment with pharmacologic doses of anti-inflammatory steroids. Thyroid and nutritional deficiencies should be corrected before initiating INCRELEX® treatment.

INCRELEX® is not a substitute for GH treatment.

The PI for Increlex includes contraindications regarding: the use of Increlex for growth promotion in patients with closed epiphyses; for use in the presence of active or suspected neoplasia; and intravenous administration. The PI also includes numerous Warnings and Precautions, including a Warning regarding the preservative, benzyl alcohol, and Precautions that Increlex has not been studied in adults or in patients less than 2 years of age, that Increlex has insulin-like hypoglycemic effects, and that lymphoid tissue hypertrophy and intracranial hypertension have been reported in patients treated with Increlex. In addition, the PI includes Precautions that patients should be monitored for slipped capital femoral epiphysis and scoliosis, and local or systemic allergic reactions may occur during treatment.

Misleading Product Claim Promotion

While not using the established name of the Ipsen/Tercica drug—Increlex—the Letter, White Paper, and Assessment Tools effectively promote this drug product. The materials discuss an FDA-approved treatment for severe Primary IGF-1 deficiency (e.g. “The FDA has approved the use of IGF-1 therapy in children with ‘severe Primary IGF-1 deficiency (IGFD)’ . . .” (Letter); “the Food and Drug Administration (FDA) has approved the use of IGF-1 in the United States in patients with severe Primary IGFD . . .” (White Paper, page 5)). Increlex, manufactured by Ipsen/Tercica, is currently the only FDA-approved IGF-1 product for this condition on the market and this fact may well be known to the target audience for these materials (including the pediatric endocrinology community) or is easily ascertainable. The White Paper also references clinical studies involving Increlex assessing different IGF-1 dosing regimens. For example, page four of the White Paper states, “Clinical investigations performed in the United States, Ecuador, Europe, and Israel, employing a variety of dosing schedules, convincingly demonstrated clinically and statistically significant growth acceleration in children receiving IGF-1,” and cites a study1 involving Increlex to support this statement. Furthermore, the Ipsen/Tercica name is featured on the first page of the White Paper (“Provided as an educational resource from Tercica, Inc., a subsidiary of the Ipsen Group”). The Assessment Tools that accompany the White Paper contain branded colors for Increlex that appear to be the same as those on other promotional materials submitted by Tercica under cover of Form FDA-2253 for Increlex, as well as the Ipsen logo. Therefore, these materials are considered product specific promotional labeling for the drug, Increlex. Consequently, these materials are subject to regulation by FDA, and, for the following reasons, are false or misleading.

Omission of Risk Information

Promotional materials are misleading if they omit material facts about the consequences that may result from the use of the drug as recommended or suggested by the materials. The Letter, White Paper and Assessment Tools present various efficacy claims for IGF-1 therapy (i.e., Increlex) (e.g., “Clinical investigations performed in the United States, Ecuador, Europe and Israel, employing a variety of dosing schedules, convincingly demonstrated clinically and statistically significant growth acceleration in children receiving IGF-1” – page 4 of the White paper), but entirely omit risk information for Increlex. By omitting the risks associated with the drug, the Letter, White Paper and Assessment Tools misleadingly suggest that Increlex is safer than has been demonstrated by substantial evidence or substantial clinical experience. Your total omission of risk information is extremely concerning from a public health perspective.

Broadening of Indication

Promotional Materials are misleading if they imply that a drug product is indicated for use in a broader range of conditions or patients than has been demonstrated by substantial evidence or substantial clinical experience. The Assessment Tools included at the end of the White Paper present charts for conditions that fall outside the realm of Increlex’s approved indication (e.g., organic growth hormone deficiency, Turner Syndrome) and contain insets which appear to indicate the response expected after one year of treatment with growth hormone for these indications. While DDMAC recognizes that these Assessment Tools are derived from publicly available sources 2,3 and present growth charts that may be used in clinical practice, they also specifically refer to uses for which Increlex has not been studied or approved. In addition, the inclusion of these insets misleadingly suggests that if the response to GH is below what one would expect in these conditions, other therapeutic options, such as Increlex, should be used. Moreover, these charts have been modified to present colors that appear to be the same as those on other promotional materials submitted by Tercica under cover of Form FDA-2253 for Increlex, the only IGF-1 product currently on the market, and to include the Ipsen logo. The charts also contain headers such as (emphasis added):

• GIRLS. . .GROWTH & GROWTH RESPONSE. . .Girls With Organic GHD (OGHD)
• GIRLS. . .GROWTH & GROWTH RESPONSE. . .Girls With Turner Syndrome

The totality of this presentation implies that Increlex can be used for a broader pediatric population than has been demonstrated by substantial evidence or substantial clinical experience.

Moreover, the White Paper also contains charts, figures, and one case study describing patients who were originally diagnosed with the condition of “idiopathic GHD” but who did not respond to growth hormone therapy, thus questioning the validity of the original diagnoses. These claims and presentations, in combination with the information provided in the text of the White Paper, misleadingly suggest that due to limitations surrounding the diagnosis of severe primary IGF-1 deficiency and the biological role that IGF plays in the overall growth process, patients who do not meet the criteria for severe Primary IGFD would still fall within Increlex’s approved indication.

In addition, the White Paper suggests IGF-1 (i.e., Increlex) should be used for the treatment of milder degrees of short stature and primary IGF-1 deficiency. Specifically, page five of the White Paper states:

It is recognized, of course, that such definitions of either short stature or low serum IGF-1 concentrations are somewhat arbitrary and reflect a dearth of data concerning the broader use of IGF-1 in patients with short stature and Primary IGFD. In light of the need for additional data, Tercica has recently completed 2 clinical trials in children with milder degrees of short stature and Primary IGFD that assessed different IGF-1 dosing and regimens, and explored the dose-dependent relationship with regard to dose escalation and response. These data are yet unpublished, and demonstrate that the evidence base for IGF-1 is still growing.

These claims, given the totality of the circumstances and the context of this branded promotional piece, misleadingly suggest that Increlex may be used in milder degrees of short stature and primary IGFD, when this is not supported by substantial evidence or substantial clinical experience. Indeed, the suggestion that Increlex may be effective in these patient populations (b)(4). Increlex is not approved for use for milder degrees of short stature and primary IGFD, and to the contrary, the Indications and Usage section of the approved PI clearly states that Increlex is only indicated for the long term treatment of growth failure in children with severe primary IGF-1 deficiency. Therefore, the statements regarding evidence of effectiveness in milder degrees of short stature and primary IGFD are misleading.

Failure to Provide Adequate Directions for Use

We note that the Letter, White Paper, and Assessment Tools do not appear to have been disseminated with the full FDA-approved product labeling (PI) for Increlex, in violation of 21 CFR 201.100(d).

Conclusion and Requested Action

For the reasons discussed above, the Letter, White Paper and Assessment Tools misbrand Increlex in violation of the Act, 21 U.S.C. 352(a) and 321(n). Cf. 21 CFR 202.1(e)(5)(i) & (iii) and (e)(6)(i). In addition, it appears that the Letter, White Paper, and Assessment Tools were not accompanied by the FDA-approved product labeling (PI) for Increlex in violation of 21 CFR 201.100(d).

DDMAC requests that Ipsen immediately cease the dissemination of violative promotional materials for Increlex such as those described above. Please submit a written response to this letter on or before November 17, 2010, stating whether you intend to comply with this request, listing all promotional materials (with the 2253 submission date) for Increlex that contain violations such as those described above, and explaining your plan for discontinuing use of such violative materials. Because the violations described above are serious, we request, further, that your submission include a comprehensive plan of action to disseminate truthful, non-misleading, and complete corrective messages about the issues discussed in this letter to the audience(s) that received the violative promotional 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 #18137 in addition to the NDA number. We remind you that only written communications are considered official. If you choose to revise your promotional materials, DDMAC is willing to assist you with your revised materials by commenting on your revisions before you use them in promotion.

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

Failure to correct the violations discussed above may result in FDA regulatory action, including seizure or injunction, without further notice.

Sincerely,
{See appended electronic signature page}
Thomas W. Abrams, RPh, MBA
Director
Division of Drug Marketing,
Advertising, and Communications
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This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature.
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/s/
----------------------------------------------------
THOMAS W ABRAMS
11/03/2010
 

_________________________________________________________________________ 

1 Chernausek SD, Backeljauw PF, Frane J, Kuntze J, Underwood LE, for the GH Insensitivity Syndrome Collaborative Group. Long-term treatment with recombinant insulin-like growth factor (IGF)-I in children with severe IGF-I deficiency due to growth hormone insensitivity. Reference ID: 2859350 J Clin Endocrinol Metab. 2007; 92(3): 902-910.
2 US DEPARTMENT OF HEALTH AND HUMAN SERVICES, Centers for Disease Control and Prevention, National Center for Health Statistics.
3 Bakker B, Frane J, Anhalt H, Lippe B, Rosenfeld RG. Height Velocity Targets from the National Cooperative Growth Study for First-Year Growth Hormone Responses in Short Children. J Clin Endocrinol Metab. 2008; 93(2): 352-357. Copyright 2009 The Endocrine Society.