Inspections, Compliance, Enforcement, and Criminal Investigations
Baxter Healthcare Corp 4/14/09
Department of Health and Human Services
|Public Health Service
Food and Drug Administration
|Center for Biologics Evaluation
1401 Rockville Pike
Rockville MD 20852-1448
April 14, 2009
VIA FACSIMILE AND CERTIFIED MAIL
RETURN RECEIPT REQUESTED
Robert L. Parkinson, Jr.
Chairman of the Board, Chief Executive Officer, and President
Baxter International Inc.
One Baxter Way
Deerfield, IL 60015-4625
Re: TISSEEL (fibrin sealant)
BLA STN: 103980
Dear Mr. Parkinson:
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 TISSEEL National Accounts Presentation (BS1846, "Presentation"), TISSEEL General Surgery Brochure (BS1791, "Brochure"), and TISSEEL Cardiac Sell Sheet (BSI974, "Sell Sheet") for TISSEEL submitted by Baxter Healthcare Corporation (Baxter) under cover of Form FDA 2253.
The Presentation, Brochure, and Sell Sheet are false or misleading because these materials, among other things, overstate the efficacy of TISSEEL and make unsubstantiated claims of superiority for TISSEEL over other conventional hemostatic agents when these have not been demonstrated by substantial evidence or substantial clinical experience. Therefore, these materials misbrand TISSEEL in violation of 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)(i),(ii), (vii) and (x).
According to the FDA-approved prescribing information (PI), TISSEEL is indicated for use as an adjunct to hemostasis in surgeries involving cardiopulmonary bypass and treatment of splenic injuries due to blunt or penetrating trauma to the abdomen, when control of bleeding by conventional surgical techniques, including suture, ligature, and cautery, is ineffective or impractical. TISSEEL is a satisfactory hemostatic agent in fully heparinized patients undergoing cardiopulmonary bypass. TISSEEL has been shown to be an effective sealant as an adjunct in the closure of colostomies.
In 2006, the current formulation of TISSEEL, vapor heated (VH) and solvent/detergent (SID) treated, was approved by FDA for introduction into the U.S. market. This new formulation replaced the earlier formulation of TISSEEL (VH only) approved in 1998.
Misleading Efficacy Claims
The Presentation (under "Efficacy" heading) contains the following misleading statement of efficacy:
"97.5% effective in achieving hemostasis in fully heparinized patients undergoing cardiopulmonary bypass 1,2"
The claim is misleading because it overstates the efficacy of TISSEEL and is not supported by substantial evidence or substantial clinical experience. The references (PI1 for TISSEEL and Rousou, et al2) cited to support the claim are inadequate. First, as shown in the table entitled "Hemostasis within 5 minutes and maintained until surgical closure" under the CLINICAL STUDIES section of its PI, TISSEEL, vapor heated, solvent/detergent (VH, S/D) demonstrated 88.2% (127/144) efficacy in the intent-to-treat analysis and 87.8% (108/123) in the per protocol analysis, which are both less than the claimed efficacy rate of"97.5%". The primary endpoint in this Phase 3, prospective, randomized, double-blind multicenter study comparing the efficacy and safety of the two formulations of TISSEEL (the earlier formulation, VH only, and the currently approved, TISSEEL, VB, SID) in 317 subjects undergoing cardiac surgery requiring cardiopulmonary bypass and median sternotomy was "hemostasis achieved at the primary treatment site within 5 minutes of treatment and maintained until closure of the surgical wound." According to the PI, "TISSEEL was non-inferior to the earlier formulation of the product using a one-sided 97.5% confidence interval on the difference in the proportion of subjects successfully treated." A confidence interval is a statistical range with a specified probability that a given measurement lies within the range; as such, it is used to indicate the reliability of this estimate. Thus, the "one-sided 97.5% confidence interval" does not equate to the claimed "97.5%" efficacy, rather it reflects a statistical measure of significance to a pre-established level of probability.
Second, the referenced article by Rousou, et al2, is inadequate to support this efficacy claim. Rousou, et al2, summarize a study that involved 333 patients undergoing reoperative surgery (redo) or emergency resternotomy. These patients were randomly assigned to initially receive the earlier formulation of TISSEEL (VB), which contained bovine aprotinin, or another conventional topical hemostatic agent. Neither treatment group received the currently approved formulation of TISSEEL, which was used in the Phase 3 study reported in the PI for TISSEEL and which replaced the bovine aprotinin with synthetic aprotinin. Notwithstanding the fact that a different product formulation and population was described by Rousou, et al2, these authors report an efficacy rate of 92.6% from this trial with TISSEEL VB, which is also less than the claimed efficacy rate of 97.5% presented for TISSEEL. Thus, the above efficacy claim is misleading because it overstates the efficacy of the currently approved formulation of TISSEEL and is not supported by the cited references.
Misleading Superiority and Clinical Significance Claims
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 such has not been demonstrated by substantial evidence or substantial clinical experience.
Specifically, the Presentation (under "Efficacy" heading) contains the following misleading statement of superiority:
"In a randomized trial, TISSEEL has been found to be superior to conventional agents during redos* and resternotomies3" ..."*(93.1% versus 12.6% success), (83.3% versus 10% success)"
The claim is misleading because it is not supported by the referenced citation. Specifically, the referenced article by Mankad, et al3 cited to support this superiority claim is inadequate. This article only provides a general discussion of the role of fibrin sealants in hemostasis, citing various clinical studies, including the above-mentioned Rousou, et al2 citation to specifically support this claim of superiority. For the same reasons already discussed above, the study by Rousou, et al2, is inadequate to support this superiority claim. In addition, notwithstanding the discussion above, the claimed efficacy rates of 93.1 % (for TISSEEL) versus 12.6% (for conventional agents) for redos in achieving hemostasis are inconsistent with the article (Rousou, et al2) cited to support these claims. According to Rousou, et al2, hemostasis was achieved in 92.6% (TISSEEL VH, the earlier formulation) vs. 12.4% (conventional topical agents) for redos.
In addition, the Presentation, Brochure and Sell Sheet also contain the following misleading statements of superiority and clinical significance:
"This concentration human fibrinogen in TISSEEL [Fibrin Sealant] - over 20 times the concentration in human plasma 1,4 - provides tensile strength up to 4 times higher than that of a high-salt, fibrin sealant with a non-physiologic clot structure.5"
"TISSEEL is the only sealant and hemostat in the U.S. containing aprotinin as an antifibrinolytic to preclude premature clot lysis....
• ...extending the life of the clot when the natural process of fibrinolysis or hyperfibrinolytic surgical situations (e.g., surgeries involving cardiopulmonary bypass or trauma) might otherwise threaten it. 1,2"
"In pre-clinical studies, the addition of aprotinin to TISSEEL was demonstrated to improve clot persistence6"
"In vitro and in vivo studies have shown that aprotinin-free sealant degrades significantly faster than that containing aprotinin 6,7"
"No competing fibrin sealant offers surgeons, this combination"
These claims are misleading because the clinical significance of enhanced clotting characteristics of aprotinin and higher tensile strength of increased concentrations of human fibrinogen in TISSEEL has not been demonstrated. Furthermore, these claims misleadingly imply that the increased clot tensile strength of TISSEEL provides superior clinical advantage over competing fibrin sealants. The referenced citations do not adequately support these claims because the data were not derived from any comparative clinical trials, and, therefore, do not constitute substantial evidence or substantial clinical experience. FDA is not aware of any such comparative clinical trials. If you have such evidence, please submit it for review.
Broadening the Indication
The Presentation and Brochunt are misleading because these materials contain the following taglines and claims that broaden the approved indication of TISSEEL:
• "Seals Tissues, Stops Bleeding" (tagline)
• "Only TISSEEL does both" (tagline)
• "TISSEEL is the only fibrin sealant that can both seal tissue and stop bleeding"
Your presentation of this information implies that your product is effective for a broader indication than FDA has approved. Specifically, these taglines and claims misleadingly imply that TISSEEL is approved as a general hemostatic agent and sealant. According to the Indications and Usage section of its PI, TISSEEL has been shown to be an effective adjunct to hemostasis in surgeries involving cardiopulmonary bypass and treatment of splenic injuries, and is satisfactory for use in fully heparinized patients undergoing cardiopulmonary bypass (emphasis added). Tisseel has also been shown to be an effective sealant as an adjunct in the closure of colostomies (emphasis added). Thus, the implied claims that TISSEEL is a general hemostatic agent and sealant are inconsistent with the PI and are not supported by substantial evidence or substantial clinical evidence.
We note that the taglines and claims are followed by a footnote that references a more complete description, located below on the same page, of the full indication. This additional information is not sufficient to mitigate the overall misleading impression that the taglines and claims create.
Conclusion and Requested Action
For reasons discussed above, the Presentation, Brochure, and Sell Sheet misbrand TISSEEL in violation of the Act, 21 U.S.C. § 352(a) and FDA's implementing regulations. Cf 21 CFR 202.1 (e)(6)(i), (ii), (vii), and (x).
We request that Baxter immediately cease the dissemination of violative promotional material for TISSEEL such as the Presentation, Brochure, and Sell Sheet 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 TISSEL such as that described above, and explaining your plan for discontinuing use of such materials. Because the violations described above are serious, we request, further, that your submission include a comprehensive plan of action to disseminate truthful, non-misleading, and complete corrective messages about the issues discussed in this letter to the audience(s) that received the violative promotional material. Please direct your response to me at the Food and Drug Administration, Center for Biologics Evaluation and Research, Office of Compliance and Biologics Quality, HFM·600, 1401 Rockville Pike, Rockville, Maryland 20852-1448. In all future correspondence regarding this matter, please refer to the BLA/STN number and to CBER-09-05. 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 TISSEEL comply with each applicable requirement of the Act and FDA implementing regulations.
Failure to correct the violations discussed above may result in FDA regulatory action, inc1uding seizure or injunction, without further notice.
Mary A. Malarkey
Office of Compliance and Biologics Quality
Center for Biologics Evaluation and Research
1 TISSEEL (Fibrin Sealant) Full Prescribing Information, 12/2007.
2 Rousou, et al. Randomized clinical trial of fibrin sealant in patients undergoing resternotomy or reoperation after cardiac operations. J Thorac Cardiovasc Surg 1989; 97: 194-203
3 Mankad, et al. The role of fibrin sealants in hemostasis. The American Journal of Surgery 182(2001):21S-28S.
4 Sierra D. Fibrin Sealant Adhesive Systems: A review of their chemistry material properties and clinical applications, Journal of Biomaterials Applications, Volume 7. April 1993:309-352.
5 Redi H, Schlag G. Properties of different tissue sealants with special emphasis on fibrinogen-based preparations. Fribrin Sealant in Operative Medicine Otorhinolaryngology. Vol. 1. 1986: 27-38.
6 Pfluger H., Lysis and absorption of fibrin sealant (Tissucol/Tisseel). In Vitro and in Vivo Experiments. Otolaryngology: Fibrin Sealants in Operative Medicine. Vol I. 1986: 39-50.
7 Pipan,C.M.,et al. Effects of antifibrinolytic agents on the lifespan of fibrin sealant. Journal of Surgical Research. 1992: 402-407.