June 9, 2009
VIA FACSIMILE AND CERTIFIED MAIL
RETURN RECEIPT REQUESTED
Pansy L. Jordan
Assistant Director, Regulatory Affairs
Lev Pharmaceuticals, Inc.
397 Eagleview Boulevard
Exton, PA 19341
Re: Cinryze (C1 Inhibitor (Human))
Dear Ms. Jordan:
The Office of Compliance and Biologics Quality (OCBQ) in the Food and Drug Administration's (FDA) Center for Biologics Evaluation and Research (CBER) has reviewed the following promotional labeling materials for Cinryze submitted by Lev Pharmaceuticals under cover of Form FDA 2253: ACAAI Bag Drop - DD0005 (Bag Drop), Cinryze Branded Panels - DD0006 (Panels), and Abridged Sales Aid - DD0023 (Sales Aid).
These promotional materials are false or misleading because they present efficacy claims for Cinryze but fail to reveal, and they minimize, material facts; they make unsubstantiated comparative claims; and they overstate the efficacy of Cinryze. Therefore, these materials misbrand Cinryze in violation of the Federal Food, Drug and Cosmetic Act (the Act) 21 U.S.C. 352(a) and 321(n), and FDA implementing regulations. Cf. 21 CFR 202.1 (e)(6)(i),(ii), and (v). These violations are problematic from a public health perspective because, by promoting misleading safety and efficacy claims, you are potentially encouraging the unsafe use of Cinryze.
Cinryze was approved by the FDA on October 10, 2008. According to the FDA-approved prescribing information (PI), Cinryze is a sterile, stable, lyophilized preparation of C1 inhibitor derived from human plasma and is indicated for the routine prophylaxis against angioedema attacks in adolescent and adult patients with Hereditary Angioedema (HAE).
Cinryze is contraindicated in patients who have manifested life-threatening immediate hypersensitivity reactions, including anaphylaxis, to the product. WARNINGS and PRECAUTIONS, included in pertinent part, in the PI are:
- Severe hypersensitivity reactions may occur. The signs and symptoms of hypersensitivity reactions may include the appearance of hives, urticaria, tightness of the chest, wheezing, hypotension and/or anaphylaxis experienced during or after injection of CINRYZE.
Because hypersensitivity reactions may have symptoms similar to HAE attacks, treatment methods should be carefully considered.
In case of hypersensitivity, CINRYZE infusion should be discontinued and appropriate treatment instituted. Epinephrine should be immediately available for treatment of acute severe hypersensitivity reaction.
- Thrombotic events have been reported in association with C1 Inhibitor products when used off-label at high doses. Animal studies have supported a concern about the risk of thrombosis from intravenous administration of C1 Inhibitor products.
- Because CINRYZE is made from human blood, it may carry a risk of transmitting infectious agents, e.g. viruses, and, theoretically, the Creutzfeldt-Jakob (CJD) agent.
In the clinical trial, the most common adverse reactions observed by ≥ 5% of the 24 evaluable subjects after receiving CINRYZE treatment were upper respiratory tract infection, sinusitis, rash, and headache.
Omission and Minimization of Risk Information
The promotional materials are false or misleading because they either fail to reveal important risk information or minimize the serious risks associated with Cinryze.
For example, the Bag Drop, Panels, and Sales Aid are false or misleading because they fail to provide any information pertaining to the potential risk of thrombotic events with the use of Cinryze. According to the WARNINGS AND PRECAUTIONS section of the PI, “Thrombotic events have been reported in association with C1 Inhibitor products when used off-label at high doses.”
In addition, the statement “[i]n rare cases there is a possibility of allergic reactions” in the Important Safety Information section of all of these materials (Bag Drop, Panels, and Sales Aid) is misleading because it minimizes the statement in the PI that: “Severe hypersensitivity may occur…Because hypersensitivity reactions may have symptoms similar to HAE attacks, treatment methods should be carefully considered…In case of hypersensitivity, CINRYZE infusion should be discontinued and appropriate treatment instituted. Epinephrine should be immediately available for treatment of acute severe hypersensitivity reaction” (emphasis added), as stated under the WARNINGS AND PRECAUTIONS section.
Similarly, the safety claim presented in the Bag Drop that Cinryze “[i]s a well tolerated treatment for routine prophylaxis against HAE attacks” (emphasis added) is misleading because there are serious risks associated with CINRYZE that are inconsistent with the claim “well tolerated”. According to the PI under Warnings and Precautions, CINRYZE prophylaxis may result in hypersensitivity reactions, thrombotic events, or may contain infectious agents because it is made from human plasma.
Misleading Comparative Claim
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 to be safer or more effective in such particular by substantial evidence or substantial clinical experience.
The Bag Drop is misleading because it presents the comparative claim that Cinryze “Provides effective routine prophylaxis without anabolic-steroid-like adverse reactions.” The reference used (Cinryze PI) to support this claim is insufficient. In fact, no such comparative statements between Cinryze and anabolic steroids are described in the PI. According to the CLINICAL STUDIES section of its PI, “[t]he safety and efficacy of Cinryze prophylaxis therapy to reduce the incidence, severity, and duration of HAE attacks was demonstrated in a single randomized, double blind, placebo controlled multi-center cross-over study of 24 patients” (emphasis added). The study did not include any anabolic steroid comparator product. FDA is not aware of any comparative clinical trials using anabolic steroids versus Cinryze in routine prophylaxis against HAE. If you have such evidence, please submit it to us for review.
Omission of Material Facts
The graphic illustrations in the Panels and Sales Aid, representing the efficacy data for Cinryze, are misleading because they fail to present relevant contextual information that efficacy was based only on 22 patients in each treatment group, and that there was a broad spectrum of self-reported outcomes in the percent reduction in attack frequency. According to Table 5 in the PI for Cinryze, the percent reduction in attack frequency during the 12 week period while patients received Cinryze ranged from -85% (i.e., a worsening, or an increase in the number of attacks by 85%) to 100% (i.e., an improvement, or a reduction in number of attacks by 100%). Thus, by failing to include the number of patients studied and the wide variation of individual response in attack frequency or lack of response, the overall presentation of study results misleadingly implies that Cinryze is more effective than has been demonstrated by substantial evidence or substantial clinical experience.
Conclusion and Requested Action
For reasons discussed above, the promotional materials misbrand Cinryze in violation of the Act, 21 U.S.C. 352(a) and 321(n), and FDA implementing regulations. Cf. 21 CFR 202.1 (e)(6)(i), (ii), and (v).
We request that Lev Pharmaceuticals immediately cease the dissemination of these materials as well as any similar violative promotional materials for Cinryze. Please submit a written response to this letter within ten (10) business days from the date of this letter. In your response, state whether you intend to comply with this request, listing all violative promotional materials for Cinryze which are similar to those described above, 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 (APLB), HFM-602, 1401 Rockville Pike, Rockville, Maryland 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 Cinryze 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