September 1, 2011
VIA FACSIMILE AND UPS WORLDWIDE EXPRESS
Regulatory Affairs Manager
Omrix Biopharmaceuticals, Inc.
Plasma Fractionation Institute
Magen David Adom Blood Services Building
Ramat Gan 52621
Re: EVICEL (Fibrin Sealant [Human])
BLA STN# 125010
Dear Ms. Hoch-Marchaim:
The Office of Compliance and Biologics Quality (OCBQ) in the Food and Drug Administration’s Center for Biologics Evaluation and Research (CBER) has reviewed two brochures, EVICEL Structured for Strength Brochure (ID# EVC-050-11-2/12) and EVICEL Factor XIII Brochure (ID# EVC-090-11-3/12), which were submitted by Omrix Biopharmaceuticals, Inc. (Omrix) for EVICEL (Fibrin Sealant [Human]) under cover of Form FDA 2253.
These promotional materials are false or misleading because they make unsubstantiated efficacy, superiority and clinical significance claims for EVICEL; thereby misbranding EVICEL under section 502(a) 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(a)(4), (e)(6)(i) and (vii).
According to the FDA-approved prescribing information (PI), EVICEL is a fibrin sealant indicated as an adjunct to hemostasis for use in patients undergoing surgery, when control of bleeding by standard surgical techniques (such as suture, ligature or cautery) is ineffective or impractical.
As stated in the DESCRIPTION section of the PI, EVICEL has two components, thrombin and Biological Active Component 2 (BAC2).
- The thrombin component contains purified human thrombin. Thrombin is a specific protease that transforms the fibrinogen contained in BAC2 into fibrin (i.e., clot). The composition of thrombin solution is as follows:
- Active ingredients: 800-1200 unit/mL human thrombin
- Other ingredients: calcium chloride, human albumin, mannitol, sodium acetate, water for injection
- The BAC2 component consists mainly of a concentrate of human fibrinogen. Fibrinogen is a protein from human blood that forms a clot when combined with thrombin. The composition of BAC2 solution is as follows:
- Active ingredients: 55-85 mg/mL concentrate of human fibrinogen
- Other ingredients: arginine hydrochloride, glycine, sodium chloride, sodium citrate, calcium chloride, water for injection
Unsubstantiated Efficacy Claims
The brochures contain the following statements:
“Strong – Stable – Secure”
“Structured for Strength – Cross-linked by Factor XIII for enhanced clot integrity”
“Strong Construction – FXIIIa contributes to increased clot strength and stability – Even before activation by thrombin, significant quantities of cross-linked fibrinogen of high molecular weight are present in EVICEL. [FXIII] adds significant resilience to fibrin clots, augmenting strength by as much as 5-fold”
“Added Confidence – EVICEL, Fibrin Sealant (Human) clot integrity helps ensure effective hemostasis during surgery and beyond”
These claims are misleading because they imply greater efficacy for EVICEL than is supported by substantial evidence or substantial clinical experience. According to the CLINICAL STUDIES section of the PI, EVICEL was studied in retroperitoneal and intra-abdominal surgery, vascular surgery, and liver surgery. In these clinical studies, efficacy was measured by time to hemostasis, not by clot integrity or clot stability
Furthermore, when presented in conjunction with the graphic image of steel structure, the above taglines misleadingly imply strength and stability when such has not been demonstrated by substantial evidence or substantial clinical experience.
Misleading Superiority and Clinical Significance Claims
The brochures contain the following statements:
“Unique formulation – Retain vital biological active clotting proteins such as fibronectin.”
“Unique Formulation – Manufactured to retain vital endogenous clotting proteins – EVICEL has the highest fibrinogen: fibronectin ratio and FXIII levels among fibrin sealants.”
“Firm Adherence – Co-polymerization of fibrinogen-fibronectin by FXIIIa significantly increases collagen binding”
“Firm Adherence – Only fibronectin-fibrinogen, co-polymerized by FXIIIa [activated FXIIIa], enabled a significant, progressive increase in the binding of fibrinogen to collagen”
Promotional materials are misleading if they contain favorable data or conclusions from nonclinical studies of a drug, such as in laboratory animals or in vitro, in a way that suggests there is clinical significance when, in fact, no such clinical significance has been demonstrated.
The above claims are misleading because they suggest that fibrinogen: fibronectin ratio and FXIII levels have a significant clinical effect on the efficacy of EVICEL when such has not been demonstrated by substantial evidence or substantial clinical experience.
Specifically, the statement “Unique formulation – Retain vital biological active clotting proteins such as fibronectin” is false because fibronectin is not a clotting protein. The cited articles are also inadequate to support the above claims. The study by Bar et al. used an in vitro tissue adherence test to determine the binding efficiency of a fibrin sealant clot to collagen based on the concentration of cross-linked fibrinogen-fibronectin molecules in the fibrinogen component of the sealant. Neither the currently approved formulation of EVICEL nor any approved competitor product was used in the study. In the study by Hickerson et al., the author demonstrated that, in vitro, EVICEL could produce a stronger and more resistant fibrin clot than TISSEEL (a competitor fibrin sealant manufactured by Baxter) because of the higher FXIII activity associated with the fibrinogen component of EVICEL. However, the authors also acknowledged that no correlation between in vitro characteristics and clinical outcomes has been established by any head-to-head clinical trials.
The brochures do contain the footnote “Based on preclinical data. The clinical significance of FXIII in the efficacy and safety of fibrin sealants has not been established.” This disclaimer is printed in very small font and is presented as a footnote at the bottom of the page and it does not mitigate the misleading benefit claims presented above.
Conclusion and Requested Actions
For the reasons discussed above, your promotional materials misbrand EVICEL under section 502(a) of the Act, 21 U.S.C. §352(a), and FDA implementing regulations, Cf. 21 CFR 202.1(a)(4), (e)(6)(i) and (vii).
We request that Omrix immediately cease the dissemination of these violative promotional materials for EVICEL, as well as promotional materials with the same or similar claims and representations. Please submit a written response 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 EVICEL, and explaining your plan for discontinuing use of such materials. Please direct your response to Dr. Lisa Stockbridge, Ph.D., 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, HFM-602, 1401 Rockville Pike, Rockville, MD 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 EVICEL 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
Director, Division of Case Management
Office of Compliance and Biologics Quality
Center for Biologics Evaluation and Research
 Bar L, Malka O, Naboichenko E, Nur I. The binding of fibrin sealant to collagen is influenced by the method of purification and the cross-linked fibrinogen-fibronectin (heteronectin) content of the ‘fibrinogen’ component. Blood Coagul and Fibrinolysis 2005; 16:111-117.
 Hickerson W, Nur I, Meidler R. A comparison of the mechanical, kinetic, and biochemical properties of fibrin clots formed with two different fibrin sealants. Blood and Coagul Fibrinolysis 2011; 22:19-23.