Inspections, Compliance, Enforcement, and Criminal Investigations
F. Vericat Cadesas 16-Mar-05
Department of Health and Human Services
Public Health Service
Center for Biologics Evaluation and Research
March 16, 2005
VIA FACSIMILE AND CERTIFIED MAIL
RETURN RECEIPT REQUESTED
F. Vericat Cadesas
2 Can Guasch St., Poligono Levante
Parets del Valles 08150
Re: BLA STN #125077
Flebogamma® 5% [Immune Globulin Intravenous (Human)]
Dear Mr. Vericat (Cadesas):
The Office of Compliance and Biologics Quality (OCBQ) in the Food and Drug Administration's Center for Biologics Evaluation and Research (CBER) has reviewed a brochure for Flebogamma® 5% [Immune Globulin Intravenous (Human)] submitted by Mr. Howard M. Smith, U. S. Agent for Instituto Grifols, under cover of Form FDA 2253 (copy enclosed). The brochure is misleading because it fails to reveal material facts regarding the risks associated with Flebogamma and, therefore, misbrands Flebogamma in violation of the Federal Food, Drug, and Cosmetic Act (the Act). See 21 U.S.C. 352(a) and 321(n) . By failing to include sufficient information on risks, you have encouraged the potentially unsafe use of Flebogamma. Instituto Grifols has also failed to submit promotional material to CBER at the time of initial dissemination, in violation of 21 CFR 601.12(f)(4).
According to the FDA-approved professional labeling (PI), Flebogamma is a highly purified (>_ 99% IgG), unmodified, human IgG that contains the antibody specificities found in the donor population. The PI states:
"Flebogamma® 5% is indicated for replacement therapy in primary (inherited) humoral immunodeficiency disorders, such as common variable immunodeficiency, x-linked agammaglobulinemia, severe combined immunodeficiency, and Wiskott-Aldrich Syndrome."
The PI also includes detailed risk information including contraindications, black box warnings, precautions, and adverse reactions. Flebogamma is manufactured by Instituto Grifols, S.A., Barcelona, Spain and distributed by Grifols Biologicals, Inc., Los Angeles, CA.
Failure to Reveal Material Facts
The brochure presents the indication for Flebogamma but fails to provide all of the necessary risk information. The omitted risk information is necessary to qualify the effectiveness claims appearing on the brochure. For example, the PI includes a black box warning regarding reports of renal dysfunction, acute renal failure, osmotic nephrosis, and death associated with the use of Immune Globulin Intravenous (Human) (IGIV) products, with those containing sucrose accounting for a disproportionate share of the total number of events (Flebogamma does not contain sucrose). We acknowledge that you have included a warning regarding products made from human plasma, though it is incomplete, and note that you refer the reader to the "enclosed full prescribing information for boxed WARNING for acute renal failure ." Referring the reader to the PI, however, is not sufficient to provide the appropriate qualification or pertinent information about the risks associated with Flebogamma. Cf. 21 CFR 202.1 (e)(3)(i).
Failure to Submit Post-Marketing Reports at the Time of Dissemination
Instituto Grifols has failed to submit its promotional material to FDA at the time of initial dissemination of such material, in violation of 21 CFR 601.12(f)(4). The Form FDA 2253 you submitted with your brochure indicates that this piece was disseminated ten months before you submitted it to FDA. You should immediately revise your procedures to ensure submission of promotional material to FDA at the time of initial dissemination of the labeling.
Conclusion and Requested Actions
Your brochure misbrands Flebogamma within the meaning of the Act because it fails to reveal material facts regarding the risks associated with the use of this product and are, therefore, misleading . See 21 U.S.C. 352(a) and 321(n) . You have also failed to submit promotional material to FDA at the time of the initial dissemination, in violation of 21 CFR 601.12(f)(4).
We request that Instituto Grifols immediately cease the dissemination of violative promotional material for Flebogamma such as described above. Please submit a written response to this letter within ten (10) business days of the date of this letter, stating whether you intend to comply with this request, listing all violative promotional materials for Flebogamma such as those described above, and explaining your plan for discontinuing use of such materials. Because the violations described above are serious, we request, further, that your submission include a plan of action to disseminate truthful, non-misleading, and complete information to the audience(s) that received
the violative promotional material . Please direct your response to me at the Food and Drug Administration, Center for Biologics Evaluation and Research, Office of Compliance and Biologics Quality, HFM-600, 1401 Rockville Pike, Rockville, Maryland 20852-1448 . In all future correspondence regarding this matter, please refer to the BLA/STN number and to CBER-05-011 . We remind you that only written communications are considered official responses.
The violations discussed in this letter do not necessarily constitute an exhaustive list. It is your responsibility to ensure that your promotional materials for Flebogamma 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.
Mary A. Malarkey
Office of Compliance and Biologics Quality
Center for Biologics Evaluation and Research