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U.S. Department of Health and Human Services

Vaccines, Blood & Biologics

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Antihemophilic Factor (Recombinant) (ReFacto)

May 23, 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 #103779
ReFacto® Antihemophilic Factor (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 the following materials submitted by Wyeth Pharmaceuticals, Inc. (Wyeth) under cover of Form FDA 2253: “PK Consumer Brochure” (209103-01) and “Consumer and HCP-HV.com 2006 Hemophilia Website” (119533-01). These materials are misleading in that they imply unsubstantiated comparative claims of safety and efficacy for ReFacto Antihemophilic Factor (Recombinant). Therefore, these materials result in the misbranding of ReFacto under section 502(a) and 502(n) of the Federal Food, and Drug, and Cosmetic Act (Act) [21 U.S.C. § 352(a) and (n)] and FDA implementing regulations (see 21 CFR 201.6(a)). These violations are concerning from a public health perspective because by promoting misleading safety and efficacy claims, you are potentially encouraging the unsafe use of ReFacto.

Background

According to the FDA-approved professional labeling (PI), ReFacto is a purified protein produced by recombinant DNA technology. ReFacto is indicated for the control and prevention of hemorrhagic episodes and for surgical prophylaxis in patients with hemophilia A (congenital factor VIII deficiency or classic hemophilia). ReFacto is also indicated for short-term routine prophylaxis to reduce the frequency of spontaneous bleeding episodes. The effect of regular routine prophylaxis on long-term morbidity and mortality is unknown.

Misleading Statements

The PK Consumer Brochure is misleading in that it suggests ReFacto and Advate® Antihemophilic Factor (Recombinant), Plasma/Albumin-Free Method are interchangeable because the pharmacokinetic (PK) profiles for these products are similar, when such interchangeability has not been demonstrated by substantial evidence or substantial clinical experience.

Specifically, the PK Consumer Brochure presents a half-page PK line graph in conjunction with the following pharmacokinetic comparability claims between ReFacto and Advate:

  • “ReFacto and Advate had similar factor VIII levels in the blood.”
  • “Recovery and half-life were similar between the products’ pharmacokinetic profiles.”
  • “There was no significant difference in recovery between ReFacto and Advate.”
  • “There was no significant difference in half-life between ReFacto and Advate.”
  • “There was no significant difference in plasma factor VIII concentration between ReFacto and Advate.”

In addition, the above claims are presented with the following statements that suggest ReFacto and Advate are interchangeable:

  • “You have a choice.”
  • “Take charge of your treatment - know your factor facts.”
  • “Remember the similarity in pharmacokinetic profiles between ReFacto and Advate.”

We note that similar claims and presentations are made on your website at www.hemophiliavillage.com (Consumer and HCP-HV.com 2006 Hemophilia Website).

The overall presentation of these claims misleadingly suggests that ReFacto and Advate have comparable clinical safety and efficacy in patients with hemophilia A and, therefore, the products are interchangeable. These claims appear in consumer-directed promotional materials that do not adequately distinguish recovery, half-life, and factor VIII levels from safety and efficacy. The basis for these claims are the PK results from a single, unblinded, randomized, single-dose, multi-center, two-period crossover bioequivalence study that included 17 evaluable male subjects aged ≥ 18 years who had documented previously treated severe hemophilia A.1

Although PK bioequivalence may suggest comparability, bioequivalence established from PK data cannot necessarily be extrapolated to suggest comparable clinical safety or efficacy between two products. In fact, according to the study’s authors, the PK study was not designed to compare clinical outcomes between ReFacto and Advate. Clinical studies are required to determine the hemostatic efficacy of antihemophilic products and are essential to evaluate, characterize, and confirm dosing requirements (e.g., amount of dose(s), time lapse to hemostatic response, number of doses needed to achieve satisfactory hemostatic response) and safety issues (e.g., treatment-emergent inhibitors, serious and non-serious adverse reactions).

We note that the PK consumer brochure states that "Clinical studies comparing efficacy/safety between recombinant products have not been conducted." However, the difference between such safety and efficacy studies and the PK studies described on that same page of the brochure is not explained.

As a result, the above misleading claims and presentation suggesting interchangeability promote the potential unsafe administration and use of ReFacto. FDA is unaware of any adequate and well-controlled clinical trials comparing the clinical safety and efficacy of ReFacto to Advate. If you have data to support such claims, please submit the data to FDA to review.

Conclusion and Requested Action

For reasons discussed above, the PK Consumer Brochure and above-referenced website misbrand ReFacto within the meaning of the Act [21 U.S.C. § 352(a) and (n)] and FDA implementing regulations (see 21 CFR 201.6(a)).

We request that Wyeth immediately cease the dissemination of the violative promotional materials for ReFacto as described above. 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, list all violative promotional materials for ReFacto which are the same as or similar to those described above, and explain 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 ReFacto 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

Enclosures:

Enclosure A -“PK Consumer Brochure” (209103-01),
Enclosure B- in part, www.hemophiliavillage.com and “HCP-HV.com 2006 Hemophilia Website” (119533-01)


 1 Di Paola, J, et al. Refacto and Advate: a single-dose, randomized, two-period crossover pharmacokinetics study in subjects with hemophilia A. Haemophilia (2007), 13, 124-130.