Our STN: BL 125392/0
OMRIX Biopharmaceuticals, Ltd.
Please refer to your biologics license application (BLA) for Fibrin Pad, submitted under section 351 of the Public Health Service Act, and to our filing letter dated January 18, 2011. While conducting our filing review we identified the following potential review issues:
1.Control of premature fibrin formation, i.e., potential interaction between biological substances on the Fibrin Pad before application to the wound site, is critical to final product quality; however, there does not appear to be an established control mechanism provided in the BLA. Please address control of premature fibrin formation on the Fibrin Pad at release and during its shelf life. If the relevant information has been submitted in the BLA, please direct our review to specific sections where this information is presented.
2. To facilitate our review of pre-clinical studies, please specify those that directly address the indication proposed in the BLA and provide a reviewer’s guide in the form of a table that indicates for each submitted study report:
- Study purpose (aspect of claimed clinical indication supported by the study).
- Study date.
- GLP/ non-GLP.
- Fibrin Pad batch number.
- Site and date of manufacture.
- Concentration of fibrinogen and thrombin components.
- Other information pertinent to characteristics / manufacture of Fibrin Pad investigated in the particular study, e.g., sterilization method used.
Please ensure that the pre-clinical studies directly addressing the proposed indication for EVARREST are submitted as complete finalized Study Reports.
3. It is noted that there are differences for the final endpoint (day) on complete absorption of the Fibrin Pad in pre-clinical reports ranging from 56 days up to 119 days (Study Reports 05-0636, 06-0658, 08-0146 and 08-0220); and these variations extend to animal models (nude mice, rats, and swine) tested. You state that the complete absorption/degradation is 56 days for clinical trial observation period. Please submit the actual number of days for complete absorption of EVARREST under “normal” conditions and “worst-case scenario” conditions as determined in pre-clinical studies or based on clinical experience (clinical observations) following EVARREST use (final clinical grade product). Please provide an explanation for differences noted in absorption rates in animals tested; and note identifiers for the product tested in each study (batch number, production site, Fibrin Pad composition). Additionally, please provide justification to establish 56 days as an accurate endpoint estimate for complete Fibrin Pad absorption in clinical trials.
4. The results of the planned analyses of effectiveness variables described in Section 8.3 of the Protocol for Study 400-07-002 do not appear to have been provided in the BLA. Please provide the results of all analyses specified in the Study Protocol.
5. Please provide copies of SAS program files used to perform study analyses and to create data tabulations and listings.
6.Please provide a more detailed rationale for your claim for a Categorical Exclusion under 21 CFR 25.31(c).
We are providing the above comments to give you preliminary notice of potential review issues. Our filing review is only a preliminary evaluation of the application and is not indicative of deficiencies that may be identified during our complete review. Issues may be added, deleted, expanded upon, or modified as we review the application. If you respond to these issues during this review cycle, we may not consider your response before we take an action on your application. Following a review of the application, we shall advise you in writing of any action we have taken and request additional information if needed.
Sincerely yours, Basil Golding, M.D.
If you have any questions, please contact the Regulatory Project Manager, Sonday Kelly, at (301) 827-6122.
Division of Hematology
Office of Blood Research and Review
Center for Biologics
Evaluation and Research
Basil Golding, M.D.