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U.S. Department of Health and Human Services

Vaccines, Blood & Biologics

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Coagulation Factor IX (Recombinant) (BeneFIX)

June 30, 2008

VIA FACSIMILE AND CERTIFIED MAIL RETURN RECEIPT REQUESTED

Mary Carpenter, Ph.D.
Director, Global Regulatory Affairs
Wyeth Pharmaceuticals, Inc.
P.O. Box 8299
Philadelphia, PA 19101

Re: BLA STN #103677/206690-01
BeneFIX [Coagulation Factor IX (Recombinant)]

Dear Dr. Carpenter:

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 flashcard ("Comparison Flashcard" 206690-01) submitted by your firm for BeneFIX under cover of Form FDA 2253; flashcard. The flashcard is misleading because it presents unsubstantiated superiority safety claims for BeneFIX. Therefore, the flashcard misbrands BeneFIX under 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)(ii). These unsubstantiated superiority safety claims are concerning from a public health perspective because they suggest that BeneFIX is safer than has been demonstrated.

Background

BeneFIX

According to its FDA-approved professional labeling (PI), BeneFIX is a purified protein produced by recombinant DNA technology and is indicated for the control and prevention of hemorrhagic episodes in patients with hemophilia B (congenital factor IX deficiency or Christmas disease), including control and prevention of bleeding in surgical settings. BeneFIX is not indicated for the treatment of other factor deficiencies (e.g., factors II, VII, VIII, and X), for the treatment of hemophilia A patients with inhibitors to factor VIII, for the reversal of coumarin-induced anticoagulation, or for the treatment of bleeding due to low levels of liver-dependent coagulation factors.

Unsubstantiated Superiority Safety Claims

The flashcard is misleading because it suggests that BeneFIX, a recombinant product, is safer than Mononine, a plasma-derived product, without support from substantial evidence or substantial clinical experience. Specifically, the front side of the flashcard includes a table comparing BeneFIX, Original BeneFIX, and Mononine with respect to "available vial sizes (IU)", "diluent volume", "reconstitution device", and "recombinant or plasma-derived product." The headline for the table includes the claim "Low diluent with recombinant safety." The comparison table misleadingly suggests that BeneFIX and Original BeneFIX, both recombinant products, are safer than Mononine, a plasma-derived product. This superior safety claim is further emphasized by the following statements on the backside of the flashcard, under the headline "Get ready for BeneFIX-Convenience with recombinant confidence":

  • "Proven viral safety"
    • "Produced through state-of-the-art recombinant DNA technology and not derived from animal or human sources"
    • "Albumin-free and plasma-free recombinant therapy"
    • "Inherently free from the risk of transmission of human blood-borne pathogens" (This claim is repeated at the bottom of the flashcard next to the name of the product)

The flashcard suggests that BeneFIX is safer than Mononine. The overall presentation suggests that there is no viral risk associated with BeneFIX and that plasma-derived products such as Mononine are virally unsafe. Yet, properly processed plasma-derived products are considered virally-safe, and cell-bank derived recombinant products may still carry viral risks related to the use of non-human (e.g., mouse, hamster, or bovine) sources in their manufacturing. In fact, adverse events for BeneFIX include Hepatitis A virus (HAV) and parvovirus B19 seroconversions, albeit the relationship of seroconversions to BeneFIX is unknown.

None of the six citations referenced adequately supports superiority claims of safety over Mononine. Three of the six citations simply reference the prescribing information for BeneFIX, Original BeneFIX, and Mononine. The pharmacokinetic study using Original BeneFIX and Mononine, referred to in the prescribing information for BeneFIX, does not constitute substantial evidence or substantial clinical experience to support the superiority safety claim for BeneFIX because this study, like most clinical pharmacology studies, was not designed to statistically evaluate the safety profile of a drug or the comparative safety profiles of multiple drugs. The three remaining references contain no clinical or pharmacokinetic data from either product.1,2,3 Two of these citations describe the processing methods used to manufacture recombinant Factor IX1,2; the other provides general recommendations concerning the treatment of hemophilia and other bleeding disorders, which the authors emphasize are not provided as medical advice for treatment of specific individuals.3 FDA is unaware of any adequate and well-controlled clinical trials comparing BeneFIX to Mononine or any data to support a claim that BeneFIX is safer than Mononine. If you have data to support such claims, please submit them to FDA.

Comparisons that represent or suggest that a product is safer or more effective than another product are misleading if not supported by data consisting of substantial evidence or substantial clinical experience. The superiority safety claims suggested by the flashcard are misleading because they are not supported by substantial evidence or substantial clinical experience.

Conclusion and Requested Action

For reasons discussed above, the flashcard presents unsubstantiated superiority claims. Accordingly, the flashcard misbrands BeneFIX in violation of the Act, 21 U.S.C. § 352(a), and FDA implementing regulations. Cf. 21 CFR 202.1 (e)(6)(ii).

We request that Wyeth immediately cease the dissemination of this flashcard as well as any same as or similar violative promotional materials for BeneFIX. Please submit a written response 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 BeneFIX, 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 numbers. 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 BeneFIX 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,

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


1 Adamson S, Charlebois T, O'Connell B, et al. Viral safety of recombinant factor IX. Semir. Hematol. 1998;35(suppl 2) 2-27.:22-27.

2 Harrison S, Adamson S, Bonam D, et al. The manufacturing process for recombinant factor IX. Semir. Hematol. 1998;35(suppl 2):4-10.

3 National Hemophilia Foundation Medical and Scientific Advisory Council (MASAC). MASAC document #165. October 2005.