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U.S. Department of Health and Human Services

Vaccines, Blood & Biologics

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Information Request Memorandum - EVARREST, May 31, 2011

Our Reference: BL125392/0

Omrix Biopharmaceuticals, Inc.
Attention: ----(b)(4)----
May 31, 2011
Sent by FAX: -----(b)(4)-----

Dear ---(b)(4)---

We are reviewing your November 19, 2010 biologics license application (BLA) for Fibrin Pad. We are providing the following comments and request for additional information to continue our review:

CMC

  1. Contents of Fibrinogen and Thrombin as presented in Table 1 Composition of Fibrin Pad (Module 3.2.P.1 Description and Composition of the Drug Product) are incongruent with those in Table 1 Fibrin Pad Release Specifications (Module 3.2.P.5.1 Specifications). For example, the target Fibrinogen content of “7.8 mg/cm2 measured as ----(b)(4)------------” may be confused with “the range ----------(b)(4)-------------- measured as ----(b)(4)-----”. Therefore, please specify in a footnote comment to Table 1 Composition of Fibrin Pad that target values for Fibrinogen and Thrombin are the average values based on analysis of N lots of Fibrin Pad in respective assays.
  1. Please explain how your dose optimization studies address and exclude overdosing of the biological drug substances that may lead to potential thrombogenicity of the Fibrin Pad. Also, please comment on how the established input dose ranges for Thrombin and Fibrinogen affect the performance of the Fibrin Pad.
  1. Please describe in detail how you establish the in-process acceptance criteria for the -----------------------------------------------------------------------------------------------------------------------------------------------------------------(b)(4)--------------------------------------------------------------------------------------------------------------------------------------------
  1. Please establish a Specification for the Matrix component of the Fibrin Pad (e.g., its -------(b)(4)-----------). The proposed Specification may be set either as an acceptance range or as a lower limit threshold.
  1. Please submit to the BLA Report Number FLC-013: Verification of the Holding Time of --------------------------------------------(b)(4)----------------------------------------------------
  1. Please provide a risk assessment on the potential immunogenicity of the Fibrin Pad due to exposure of its components to -(b)(4)- solvent and e-beam sterilization, with references to specific sections of the BLA containing the relevant Study Reports.
  1. Please submit to the BLA up-to-date stability data for the Fibrin Pad Validation Batches ---------------------(b)(4)-----------------------------------
  1. In your stability studies, we note different trends for the ----------------(b)(4)----------------- for Pivotal Lot L11F284 and in ----(b)(4)---- for Pivotal Lot M06F164 when compared to other lots. We also note that these 2 lots were used in Clinical Study 400-07-002 in which several adverse events had occurred. Please explain the aberrant stability trends, and comment on the potential correlation between these two observations.

Preclinical

  1. Based on the review of pharmacological and toxicological data presented by the sponsor, the following information is requested:

There appears to be an outstanding safety concern related to the long-term presence of the product (due to its slow degradation) particularly in malignant patients related to potential carcinogenesis. It is noted that EVARREST can remain in situ > 60+ days following inflammation and possibly adhesion and thrombotic events post-surgery. Therefore, we recommend the sponsor perform a well-powered and controlled study to determine the carcinogenicity potential as well as the mechanism of cancer development in an animal model following use of EVARREST. For further guidance please refer to ISO 10993, ICH S1A, ICH S1B and ICH S1C(R2), which can be found at http://www.fda.gov/cder/Guidance/5544fnl.htm

Clinical

  1. Please provide estimated VTE (venous thromboembolism) risk scores, based on the Ethicon VTE risk presented in the BLA, for all patients in the safety analysis set.
  1. Please provide a list of the specific sites where the fibrin pads were placed in all patients who were treated with the fibrin pad. This information should have been recorded in the eCRF. Please submit the dictated operative notes for all subjects in the safety analysis set. Please present this information in a table listing the patient number and sites/locations for the FP (target bleeding sites [TBS] and non-TBS).
  1. Please present a dataset consisting of all AEs according to body cavity (e.g. thoracic, abdominal, retroperitoneal, pelvic), and surgical procedure for each subject.
  1. Please provide a summary table of efficacy for each body cavity (abdominal, retroperitoneal, thoracic and pelvic) according to treatment allocation (FP vs Surgicel).
  1. Labeling comments will be communicated pending further review of the BLA.
  1. If available, please submit additional safety information from the soft tissue surgery study being conducted outside the US, as well as any other studies in which the fibrin pad is being evaluated.
  1. Please submit a formal request to defer all pediatric studies.
  1. Please submit a pediatric deferral plan that includes, but not limited to, a general investigational plan for studying the fibrin pad in the pediatric population. Please specify the age groups to be studied, clinical setting and dosing. In addition, please provide an estimate of the number of pediatric patients you plan to study.

The review of this submission is on-going and issues may be added, expanded upon, or modified as we continue to review this submission.

Please submit your response or a partial response as an amendment to this file by July 5, 2011 referencing the date of this request. If you anticipate you will not be able to respond by this date, please contact the Agency immediately so a new response date can be identified.

If we determine that your response to this information request constitutes a major amendment, we will notify you in writing. If we receive your major amendment during the last three months of the review period, we will extend the review period an additional three months.

The action due date for this file is September 19, 2011.

If you have any questions, please contact me at (301) 827-6122.

Sincerely,

Sonday L. Kelly, M.S.
Regulatory Project Manager
FDA/CBER/OBRR/DBA/RPMB