July 7, 2008
VIA FACSIMILE AND CERTIFIED MAIL
RETURN RECEIPT REQUESTED
Associate Director, Global Regulatory Affairs
Baxter Healthcare Corporation
One Baxter Way
Westlake Village, CA 91362
FEIBA VH (Anti-Inhibitor Coagulant Complex, Vapor Heated)
Dear Ms. Lucas:
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 "Clinical Thank You Email" (---------------"Email") for FEIBA VH submitted by Baxter Healthcare Corporation (Baxter) under cover of Form FDA 2253 . This Email makes false or misleading safety and efficacy claims for FEIBA VH. Therefore, this material misbrands FEIBA VH 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) and (iv). 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 FEIBA VH.
According to the FDA-approved prescribing information (PI), FEIBA VH is a freeze-dried sterile human plasma fraction with Factor VIII inhibitor bypassing activity and is indicated for the control of spontaneous bleeding episodes or to cover surgical interventions in hemophilia A and hemophilia B patients with inhibitors. FEIBA VH is contraindicated in patients who are known to have normal coagulation mechanism.
Misleading Efficacy Claim
This Email letter contains the following misleading statement of efficacy under the first bulleted section:
"Controlled 78% of bleeds with 3 or fewer infusions-60% of which were controlled with 1 infusion within 12 hours"
The claim is misleading because it overstates the efficacy of FEIBA and the claimed efficacy rate of 60% with one infusion is inconsistent with the PI. According to the PI, "In 130 (78%) of the episodes, hemostasis was achieved with one or more infusions. of these, 36 % were controlled with one infusion within 12 hours" (Clinical Pharmacology). Additionally, the above claim is false or misleading because it only presents that FEIBA "controlled 78% of bleeds with 3 or fewer infusions," but omits important contextual information that the bleeds were controlled "within 36 hours." By omitting this information, the overall presentation of the claim misleadingly suggest that 60% of the bleeds were controlled within 12 hours, which is false.
Misleading Safety Claims
This Email letter contains the following misleading statement under the third bulleted section:
"FEIBA is well tolerated in 96%-100% of infusions with a low thrombotic event incidence (0.008%)"
The safety claim that FEIBA is "well tolerated" in 96-100% of infusions and has a low incidence of thrombotic events (0.008%) is misleading because it minimizes the fact that serious thrombotic events can occur with FEIBA. Similarly, under the Important Safety Information, the use of the phrase "in rare instances" to describe thrombotic events also minimizes this risk. Specifically, the PI Warnings section contains, in pertinent part, safety information that "thromboembolic events may occur in the course of treatment . particularly following the administration of high doses and/or in patients with thrombotic risk factors," and "patients .must be monitored for the development of DIC [disseminated intravascular coagulation] and/or symptoms of acute coronary ischemia". These risks are further elaborated upon in the Adverse Reactions section of the PI. Furthermore, the Aledort1 citation provided to support the low incidence rate (0.008%) of thrombotic events is based on postmarketing reports, which are not considered substantial evidence because they are voluntarily reported, are from a population of uncertain size, and it is not always possible to reliably estimate the frequency of the adverse event or establish a causal relationship to the product. Therefore, the safety claim above and the use of the term "rare" are misleading because these claims are inconsistent with the PI and are not supported by substantial evidence or substantial clinical experience.
Moreover, the following adverse events, but not limited to, that are reported in the referenced studies1-5 to support the safety claim are inconsistent with the term "well-tolerated":
- "Seven minor adverse reactions, including minor chest pain and tightness, drowsiness, and discomfort in breathing" and "evidence of liver dysfunction was seen in three patients."2
- "chills, fever, nausea, dizziness, and an unusual taste in the mouth" 3
- "Three patients contracted clinically overt hepatitis."4
- "For FEIBA there were 40 total reports [MedWatch Reports], of which 11 [>25%] were thrombotic events." 1
- ".a myocardial infarction occurred one hour after the second infusion of FEIBA in a 41-year-old hemophilia B patient.The second dose .increased the circulating Factor IX level until 58%. The combination between this increase in plasma coagulant activity and pre-existing risk factors.might have been responsible for the thrombotic complication." 5
As a result, the above statements promote the potential unsafe administration and use of FEIBA. If you have adequate and well controlled data to support such claims, please submit the data to FDA to review.
Conclusion and Requested Action
For reasons discussed above, the Email letter misbrands FEIBA VH 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) and (iv).
We request that Baxter immediately cease the dissemination of this Email letter as well as any same as or similar violative promotional materials for FEIBA VH. 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 FEIBA VH, which are the same as or 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 FEIBA VH 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/
Robert A. Sausville
Director, Division of Case Management
Office of Compliance and Biologics Quality
Center for Biologics Evaluation and Research
1 Aledort LM. Comparative thrombotic event incidence after infusion of recombinant factor Vlla versus factor VIII inhibitor bypass activity. J Thromb Haemost. 2004; 2: 1700-1708.
2 Hilgartner M, Aledort L, Andes A, Gill J, and the members of the FEIBA Study Group. Efficacy and safety of vapor-heated anti-inhibitor coagulant complex in hemophilia patients. Transfusion. 1990; 30: 626-630.
3Hilgartner MW, Knatterud LG, and the FEIBA Study Group. The use of factor eight inhibitor by-passing activity (FEIBA Immuno) product for treatment if bleeding episodes in hemophiliacs with inhibitors. Blood. 1983; 61 (1): 36-40.
4 Sjamsoedin LJM, Heijnen L, Mauser-Bunschoten EP, et al. The effect of activated prothrombin complex concentrate (FEIBA) on joint and muscle bleeding in patients with hemophilia A and antibodies to factor VIII. N Engl J Med. 1981; 305 (13): 717-721.
5 Negrier C, Goudamand J, Sultan Y, Bertrand M, Rothschild C, Lauroua P, and members of the French FEIBA study Group. Multicenter Retrospective study on the Utilization of FEIBA in France in Patients with Factor VIII and Factor IX Inhibitors.