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U.S. Department of Health and Human Services

Vaccines, Blood & Biologics

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Coagulation Factor IX (Human) (Mononine)

September 26, 2007

VIA FACSIMILE AND CERTIFIED MAIL
RETURN RECEIPT REQUESTED

Paul Hartmann, R.Ph.
Senior Director, Regulatory Affairs
CSL Behring LLC
P.O. Box 61501
King of Prussia, PA 19406-0901

Re: BLA STN # 103957/5142, 5144
Mononine® [Coagulation Factor IX (Human)]

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 direct to consumer promotional brochure (10#102-11340, Enclosure A) and Internet website www.HemophiliaB.com (Enclosure B) for your product Mononine® [Monoclonal Antibody Purified Coagulation Factor IX (Human)] (Mononine®) submitted by your firm under cover of Form FDA 2253. These materials result in the misbranding of Mononine® under sections 502(a) and 502(n) of the Federal Food, and Drug, and Cosmetic Act (Act) (21 U.S.C. §§ 352(a) and 352(n)), because they both make unsubstantiated superiority claims (Cf. 21 CFR 202.1 (e)(6)(ii)). By promoting unsubstantiated superiority claims, you are potentially encouraging the unsafe use of Mononine®.

Background

According to the FDA-approved professional labeling (PI), Mononine® is a sterile, stable, lyophilized concentrate of Factor IX prepared from pooled human plasma and, according to the Indications and Usage section of the PI, is intended for the prevention and control of bleeding in Factor IX deficiency, also known as Hemophilia B or Christmas disease. Mononine® is not indicated for the treatment or prophylaxis of Hemophilia A patients with inhibitors to Factor VIII, nor is it indicated in the treatment or reversal of coumarin-induced anticoagulation or in a hemorrhagic state caused by hepatitis-induced lack of production of liver dependent coagulation factors.

Unsubstantiated Superiority Claims

The two referenced promotional materials contain efficacy comparisons of two different coagulation factor IX products, Mononine (human plasma derived) and BeneFIX (recombinant purified protein), that are false or misleading. Specifically, the second page of the direct to consumer brochure includes the headline:

"Learn how you'll Double the Recovery with Mononine®", followed by the text:

"Mononine® is a factor IX (F IX) replacement therapy that has been demonstrated in studies to provide double the recovery of a leading recombinant F IX therapy.2 As a result you'll need fewer units of Mononine® to achieve the same F IX plasma levels as you would with the recombinant F IX.2 That's important for people who want to stay active but who experience a low recovery level."

Reference 2, cited above, is a pharmacokinetic analysis comparison study by Ewenstein et al., of plasma-derived and recombinant F IX.

In addition, the fourth page of the brochure includes the headline:

"It's time to explore HemophiliaB.com" with text that directs the consumer to: "Log on today for answers to your questions, the latest information and reasons why you should consider Mononine® as your F IX replacement therapy." When the consumer goes to the website and clicks on the "The MONONINE DIFFERENCE" the following headline appears, " Mononine® is Effective. Studies have shown that Mononine® is more effective than BeneFIX in increasing factor IX recovery levels in people with hemophilia B. Doctors tested patients with moderate or severe hemophilia B to see if there was a difference in their factor IX recovery levels after receiving infusions of either Mononine® or BeneFIX." with this text being followed by a boxed message containing the headline, "Mononine® - Double the Recovery vs. BeneFIX" and a bar graph showing Mononine and BeneFIX recovery rates of 1.71 (± 0.73) IU/dL per IU/kg and 0.86 (±0.31) IU/dL per IU/kg), respectively. The bar graph is followed with the comments:

  • "Mononine® has double the recovery of BeneFIX.
  • Recovery differences can have important treatment implications.
  • Fewer units of Mononine® are required to achieve the same factor IX levels as BeneFIX.
  • Mononine® stays in the blood longer and keeps working to prevent bleeding between infusions."

Drug comparisons that represent or suggest that a product is more effective than another product are false or misleading if not supported by data consisting of substantial evidence or substantial clinical experience. The above-referenced effectiveness claims are false or misleading because they are derived from data that suggest substantial clinical experience or substantial evidence when in fact neither has been demonstrated. More specifically:

  • the promotional materials suggest that Mononine® is superior to BeneFIX due to in-vivo recovery (IVR) rates as reported in the Ewenstein study. However, IVR only predicts the immediate response, or peak level, of coagulation factor after intravenous injection (or short infusion) and, therefore, does not tell us about the overall efficacy of Mononine® as compared to BeneFIX.

     

     

  • the statement "Mononine® stays in the blood longer and keeps working to prevent bleeding between infusions" is false or misleading because it is contradicted by evidence you cite in your promotional materials (namely, the Ewenstein study) which states that the half-life of BeneFIX is approximately two hours longer than the half-life of Mononine®. Furthermore, the half-life information contained in the Ewenstein study is, itself, inconsistent with the half-life information contained in the PI for Mononine.

     

Therefore, the conclusions drawn by your firm regarding the relative effectiveness of Mononine® and BeneFIX cannot be substantiated. In addition, given the improper foundation upon which the results were based, your claims present a public safety concern because they could influence a switch from BeneFIX to Mononine® and encourage the use of a reduced dose of Mononine® that may potentially be life-threatening.

Conclusion and Requested Action

Your direct to consumer brochure and internet website www.HemophiliaB.com misbrand Mononine® within the meaning of sections 502(a) and 502(n) of the Act (21 U.S.C. §§ 352(a) and 352(n) ), (Cf. 21 CFR 202.1(e)(6)(ii)) because they both make unsubstantiated superiority claims regarding Mononine®.

We request that CSL Behring immediately cease the dissemination of the violative promotional material for Mononine® 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 Mononine® 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 Mononine® 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.

Sincerely,

----- signature -----

Robert A. Sausville
Director, Division of Case Management
Office of Compliance and Biologics Quality
Center for Biologics Evaluation and Research

Enclosures:

Enclosure A- Direct to Consumer brochure (10#102-11340)
Enclosure B-www.HemophiliaB.com website