March 05, 2010
VIA FACSIMILE AND CERTIFIED MAIL
RETURN RECEIPT REQUESTED
Paul R. Hartmann, RPh.
Senior Director, Regulatory Affairs
CSL Behring LLC
1020 First Avenue
P.O. Box 61501
King of Prussia, PA 19406-0901
Re: Zemaira (Alpha1 Proteinase Inhibitor (Human))
BLA STN# 125078
Dear Mr. Hartmann:
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 Sales Aid entitled, Recognizing AATD (ID # 9Z087), for Zemaira (Alpha1 Proteinase Inhibitor (Human)) submitted by CSL Behring LLC (CSL) under cover of Form FDA 2253.
This promotional material is false or misleading because it overstates the efficacy and makes misleading comparative claims for Zemaira. Therefore, this material misbrands Zemaira under section 502(a) of the Federal Food, Drug, and Cosmetic Act (the Act), 21 U.S.C. §352(a), and FDA implementing regulations, Cf. 21 CFR 202.1(e)(6)(i), (6)(ii), and (x).
According to the Indications and Usage section of the FDA-approved prescribing information (PI), Zemaira is indicated for chronic augmentation and maintenance therapy in individuals with alpha1-proteinase inhibitor (A1-PI) deficiency and clinical evidence of emphysema. Zemaira increases antigenic and functional (ANEC) serum levels and lung epithelial lining fluid levels of A1-PI. Clinical data demonstrating the long-term effects of chronic augmentation therapy of individuals with Zemaira are not available. Safety and effectiveness in pediatric patients have not been established. Zemaira is not indicated as therapy for lung disease patients in whom severe congenital A1-PI deficiency has not been established.
Zemaira is contraindicated in individuals with a known hypersensitivity to any of its components. Zemaira is also contraindicated in individuals with a history of anaphylaxis or severe systemic response to A1-PI products. Individuals with selective IgA deficiencies who have known antibodies against IgA (anti-IgA antibodies) should not receive Zemaira, since these patients may experience severe reactions, including anaphylaxis, to IgA that may be present in Zemaira.
The Warnings section of the PI includes, but is not limited to, the following:
Zemaira is made from human plasma. Products made from human plasma may contain infectious agents, such as viruses, that can cause disease. Because Zemaira is made from human blood, it may carry a risk of transmitting infectious agents, e.g., viruses, and theoretically the Creutzfeldt-Jakob disease (CJD) agent. The risk that such products will transmit an infectious agent has been reduced by screening plasma donors for prior exposure to certain viruses, by testing for the presence of certain current virus infections, and by inactivating and/or removing certain viruses during manufacture. The manufacturing procedure for Zemaira includes processing steps designed to reduce further the risk of viral transmission. Despite these measures, such products may still potentially contain human pathogenic agents, including those not yet known or identified. Thus, the risk of transmission of infectious agents can not be totally eliminated.
In clinical studies, the following treatment-related adverse reactions were reported: asthenia, injection, site pain, dizziness, headache, paresthesia, and pruritus. Each of these related adverse events was observed in 1 of 89 subjects (1%).
Misleading Efficacy Claims
Promotional materials are misleading if they represent or suggest that a product is more effective than has been demonstrated by substantial evidence or substantial clinical experience. Specifically, the Sales Aid contains the following misleading statements [bolded for emphasis]:
- “Early use of pharmacotherapy that may slow decline of pulmonary function.”
- “Alpha1 augmentation therapy significantly reduced lung function decline in patients with a mean FEV1 of 35% to 49%.”
The above cited claims, “slow decline of pulmonary function” and “reduced lung function decline,” are misleading because they are inconsistent with the PI and misleadingly imply that Zemaira has demonstrated protective effects in the lungs or improved pulmonary function when such has not been demonstrated by substantial evidence or substantial clinical experience. According to the Indications AND USAGE section of the PI, “Zemaira is indicated for chronic augmentation and maintenance therapy in individuals with alpha1-proteinase inhibitor (A1-PI) deficiency and clinical evidence of emphysema (emphasis added)” and “clinical data demonstrating the long-term effects of chronic augmentation therapy of individuals with Zemaira are not available.” Additionally, the CLINICAL PHARMACOLOGY section of the PI states, “the hypothesis that maintaining a serum level of antigenic A1-PI will restore protease-antiprotease balance and prevent further lung damage has never been tested in an adequately-powered controlled clinical trial.”
Furthermore, the overall graphic presentation of the “Mean FEV1 Decline (mL/yr)” that compares two bar graphs for mean FEV1 decline in patients not receiving therapy (93.2 mL) vs. patients receiving therapy (66.4 mL), in conjunction with the efficacy claim, “Alpha-1 augmentation therapy significantly reduced lung function decline in patients with a mean FEV1 of 35% to 49%,” is misleading because it is inconsistent with the PI and suggests that Zemaira has been demonstrated to reduce lung function decline when such has not been demonstrated by substantial evidence or substantial clinical experience. As noted above, the PI states that there are no clinical data demonstrating long-term effects of chronic augmentation therapy with Zemaira. Moreover, the citation provided to support the reduction in lung function decline is based on a non-randomized registry study, which is not considered substantial evidence to support the claim.
Misleading 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 in some particular when it has not been demonstrated by substantial evidence or substantial clinical experience. Specifically, the Sales Aid presents a prominent, bolded headline, “Unmatched purity. And peace of mind” with a comparative table of A1-PI protein (lot release and shelf-life specification) in Prolastin vs. Zemaira, -(b)(4)- vs. -(b)(4)- (lot release) and “unknown” vs. -(b)(4)- (shelf-life), respectively. The overall comparative presentation is misleading because it suggests that Zemaira is superior or more effective than Prolastin based on a higher concentration of A1-PI protein when such has not been demonstrated by substantial evidence or substantial clinical experience.
Additionally, the Sales Aid presents the following misleading comparative efficacy claim presented under the prominent, bolded headings “Efficacy. Pure. And Simple.” and “Effective”:
“In a retrospective analysis of the pivotal clinical trial Zemaira patients were 3 times less likely to experience COPD exacerbations than Prolastin patients.”
The conclusion that Zemaira-treated patients experienced 3 times less COPD exacerbations than Prolastin patients is misleading because it suggests that Zemaira is more effective than Prolastin, when such has not been demonstrated by substantial evidence. As you noted above, these results are based on a retrospective analysis. According to the Adverse Reactions section of the PI, “No clinically significant differences were detected between the two treatment groups.”
Likewise, you present the following misleading safety claim under the prominent, bolded headings, “Safety. And tolerability.” and “Well tolerated”:
“During clinical trials, Zemaira patients reported 6 times fewer infusion-related adverse events than Prolastin patients.”
The conclusion that Zemaira patients had 6 times fewer adverse events is misleading because it implies Zemaira is safer when there was no clinically significant difference in adverse events between treatment groups. Although you present a disclaimer, in very tiny footnote at the very bottom of the page, “no clinically significant differences were detected between the two treatment groups,” this disclaimer does not mitigate the overall misleading impression that the claim conveys.
Conclusion and Requested Actions
For the reasons discussed above, your promotional materials misbrand Zemaira under section 502(a) of the Act, 21 U.S.C. §352(a), and FDA implementing regulations, Cf. 21 CFR 202.1(e)(6)(i), (6)(ii), and (x).
We request that CSL immediately cease the dissemination of these violative promotional materials for Zemaira, as well as promotional materials with the same or similar claims and representations. Please submit a written response 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 Zemaira and explaining your plan for discontinuing use of such materials. Please direct your response to Ms. Ele Ibarra-Pratt, RN, MPH, Branch Chief at the Food and Drug Administration, Center for Biologics Evaluation and Research, Office of Compliance and Biologics Quality, Division of Case Management, Advertising and Promotional Labeling Branch, HFM-602, 1401 Rockville Pike, Rockville, MD 20852-1448. In all future correspondence regarding this matter, please refer to the BLA/STN number. 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 Zemaira comply with each applicable requirement of the Act and FDA implementing regulations.
If you choose to revise your promotional materials, APLB is willing to assist you in assuring that your revised materials comply with applicable provisions of the Act by reviewing your revisions before you use them in promotion.
Robert A. Sausville
Director, Division of Case Management
Office of Compliance and Biologics Quality
Center for Biologics Evaluation and Research
The Alpha-1-Antitrypsin Deficiency Registry Study Group. Survival and FEV1 decline in individuals with severe deficiency of α1-antitrypsin. Am J Resp Crit Care Med. 1998;158:49-50.