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Vaccines, Blood & Biologics

Record of Telephone Conversation, September 19, 2012 - EVARREST


Submission Type: BLA    Submission ID: 125392/0    Office: OBRR


Fibrin Sealant Patch [EVARREST]


Ethicon, Inc.

Telecon Date/Time: 19-Sep-2012 01:00 PM        Initiated by FDA? No

Telephone Number: --b(4)--------, Participant Code: --b(4)--------

Communication Categorie(s):

1. Other – Labeling negotiations

Author(s): TRACY TILGHMAN/Kimberly Lindsey, Natalya Ananyeva

Telecon Summary:

Teleconference to discuss with Ethicon the contents of Prescribing Information for EVARREST.

FDA Participants:

Kimberly Lindsey

Loan Nguyen

Kristine Khuc

Lisa Stockbridge

Natalya Ananyeva

Tracy Tilghman


Non-FDA Participants:

Jessica Chung

Jerome Riebman

Samson Tom



Jessica Shen

Jonathan Batiller




Trans-BLA Group: No

Related STNs: None


Related PMCs: None


Telecon Body:


The purpose of this teleconference is to discuss the latest version of the Prescribing Information (PI) for EVARREST submitted by Ethicon, Inc. (Ethicon) to FDA on 18 September 2012 by e-mail (the PI is attached to this record) in preparation to formal submission to the BLA file (response to the Information Request dated 11 September 2012).  FDA also received the questions for clarification from Ethicon regarding the PI and prepared clarification on major issues of their concern (the files are attached) which were discussed during the teleconference. 


The first clarification was for the Indications for use section of the PI. Ethicon proposed to remove the phrase “manual compression” and replace the term “non-cardiac thoracic surgery” with the term “general thoracic surgery”.  FDA stated that manual compression is a condition of use for EVARREST and therefore this phrase should remain in the Indications section.  Regarding the use of “non-cardiac surgery” versus “general thoracic surgery”, FDA recommends that Ethicon uses the term “thoracic (non-cardiac)” to denote that the indication for thoracic surgery excludes cardiovascular surgery, which is also a thoracic surgical procedure. The use of the term “general thoracic” is too inclusive and implies that cardiovascular/ carothoracic surgery is an indication. ----------b(4)----------------------------------------------------------------------------------------------------------------


Ethicon stated that the “manual compression” phrase appears unnecessary in the Indications section as it is spelled out in the Instructions for use section. Ethicon questioned FDA about any examples of products where this wording is included in the Indications for use statement. To their knowledge, this statement is not currently used with other approved products in this class.  FDA stated that certain issues with the wording in the PI pertaining to similar products that have been approved can be revised in current and future submissions. At this time, FDA considers it important to emphasize that EVARREST (which belongs to the Fibrin Sealant Patch class) should be used with manual compression, and this statement should remain in the Indications section. FDA emphasized that this recommendation has been already discussed with the first line clinical supervisor and thus is beyond the initial reviewer level.


Ethicon questioned if they could remove the “non-cardiac thoracic surgery” statement from the Indications section of the PI and add a statement “the use of EVARREST during thoracic surgery has not been evaluated” in an appropriate section of the PI.  FDA stated that while this additional explanation can be provided later on in the PI, FDA recommends that in the Indications section of the PI Ethicon refers to the patient population that was studied in clinical trials, i.e., non-cardiac thoracic surgical patients. Ethicon stated they will take this recommendation into consideration.


FDA discussed the Limitations of Use section of the PI, stating that the neonatal population was included in the waiver presented at the Pediatric Advisory Committee, and the decision of the Committee is considered legally binding.  FDA emphasized a potential technical difficulty in the application of the product in the neonate population and therefore recommends highlighting the neonate population under the pediatric use section and throughout the PI.  FDA questioned whether Ethicon considered a specific neonatal population for which the product will be studied. Ethicon stated that they have no immediate plans on evaluating the product in the neonate population, and excluded this population in their European application.  FDA described potential safety concerns with the use of EVARREST in neonatal surgical applications. FDA stated that often neonates are subjected to staged or repeat operations due to congenital anomalies. It is conceivable that if EVARREST was used in an initial surgical setting and a neonatal patient required a repeat operation in a short period of time (before the patch was fully absorbed), remnants of the patch might still be present from the initial operation. Because the neonates often undergo staged operations requiring the surgeon to re-operate near the original operative site, adhesions or other events resulting from an incompletely absorbed implanted foreign device may occur. It is FDA opinion that potential formation of adhesions should be highlighted in the package insert under the pediatric usage statement which would further explain the neonatal use limitations.  FDA re-stated that the pediatric use information must remain under Limitations of Use. 


Ethicon asked what FDA main concern was regarding the potential of adhesion formation with the use of EVARREST.  --------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------(b)(4)------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------


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Ethicon asked if the ORC statement can be moved from Limitations of Use section to the Warnings and Precautions section of the Pi for EVARREST, and if an alternative language can be used for the ORC statement.  --------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------(b)(4)-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------.


FDA stated that this aspect has been discussed at the supervisory level, and considering potential labeling concerns and potential off-label use of the product, FDA strongly recommends including the ORC cautionary statement in the PI for EVARREST. FDA recommended that Ethicon submit a summary of their updated preclinical data as supportive evidence to better inform the FDA and to alleviate the concern of adhesion formation with EVARREST. FDA agreed that this cautionary statement can be placed in the Warnings and Precautions section of the PI. Ethicon will propose the language for the ORC statement.


FDA emphasized that the information package from Ethicon will be reviewed by additional FDA personnel, and the reviewers will seek the input from the supervisory level to continue the labeling negotiations.


FDA agrees that other statements initially suggested under Limitations of Use (such as “renal pelvis” and “ureter procedures” statement) may be presented under Warnings and Precautions.


Regarding the Dosing and Administrations section, FDA has no objections to the added illustrations.


Ethicon asked if the statement regarding the patch packing can be removed: the wording “do not leave” and “exercise care to avoid overpacking” may be confusing because the product is designed to remain on the wound surface after application.


FDA explained that this statement relates to the concern of potential inappropriate use of the patch to pack irregular deep surfaces (e.g., metastasectomy sites). To prevent this inappropriate use, FDA recommends a statement in the Instructions for use section.  FDA proposed the alternative wording such as “use the minimal amount to achieve hemostasis” or “do not pack” as more accurate and clear.  FDA recommended using the statement “do not pack”, as command language in the PI would be most effective in emergency and surgery situations. Ethicon stated that they will consider the FDA-proposed wording or propose an alternative wording.  


FDA stated that in order to avoid redundancy, the animal toxicology information could be presented in the Pharmacokinetics section.  However, FDA recommends retaining in the PI the statement that 95% of the patch is absorbed within 8 weeks, with a residual 5% (approximately) of the patch being absorbed exponentially over time.  Ethicon stated that in their opinion, the wording “complete absorption” is sufficient as all of their preclinical studies have demonstrated        “complete absorption” of EVARREST patch at or around 8 weeks (56 days). The “complete absorption” is defined as approximately 90% of the patch being absorbed with <10% of the remaining material, which is within the range of biological variability. FDA recommended that Ethicon submits their justification to FDA for review by the appropriate discipline reviewer. Ethicon stated they will provide such a justification.


FDA stated the position of the Product Office regarding terminology for the device component of EVARREST.  FDA agrees that the definition of EVARREST as “a combination product” should be stated in the PI. FDA proposed the term for the device component as a “backing layer” and considers that it accurately describes the product composition and the functional role of the device component which provides mechanical integrity and strength. This term also allows discriminating between the device (“backing layer”) and the final product (“fibrin sealant patch” which is the combination of the backing layer and embedded biologics). In the term proposed by Ethicon, “flexible composite patch component”, this discrimination between the device and the product is lost. The term appears confusing because “patch component” has two components (ORC and PG910). If Ethicon decides to stay with their term, FDA recommends shortening it to “flexible composite patch”, and using it in full at first mentioning in respective sections, followed by abbreviation afterwards (“patch component” or “patch”). FDA stated that these are recommendations only, and that Ethicon will make the final decision on the term. Ethicon stated that they will discuss FDA recommendations internally and provide the final term in their revisions to the PI.


FDA emphasized that their comments to the PI are in accordance with the regulations, and recommended that Ethicon review 21 CFR 201.57 regarding requirements for the contents and the format of the PI. Specifically, FDA stated that Ethicon should avoid inappropriate use of the phrase “do not use”. Ethicon agreed to these recommendations.  FDA recommended that Ethicon put together their rationales/proposals for the remaining discussion items and submit this information together with the revised PI for FDA review no later than Friday, September 21, 2012. Ethicon agreed that this deadline is appropriate and committed to provide the proposals for clarification points and the revised PI, in addition to the carton and container label in SPL format, by September 21, 2012.


FDA reiterated that the revised labeling will need to be reviewed by additional FDA personnel.


FDA stated that they need clarification on the completed Lot Release Protocols which are currently under review by Product Release Branch. The reviewers need to clarify whether the difference in the dating periods stated for the conformance lots (12 months) and later lots (24 months) is related to the amount of stability data available at that time. Ethicon stated that this is correct and will provide a written clarification by Friday, September 21, 2012.


Ethicon questioned whether there are additional post marketing commitments (PMCs) that may be requested by FDA. FDA confirmed the receipt of Ethicon’s commitment to three PMC studies in Amendment 125392/0.27 and does not have any additional requests at this time. However, if any additional information is needed, FDA will notify Ethicon immediately.



Page Last Updated: 09/23/2013
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