RECORD OF TELEPHONE CONVERSATION
Submission Type: BLA Submission ID: 125392/0 Office: OBRR
Telecon Date/Time: 24-Sep-2012 02:00 PM Initiated by FDA? Yes
Telephone Number: --b(4)---------, Participant Code: --b(4)-------
1. Other – Proper Name discussion
Author: TRACY TILGHMAN
Teleconference to discuss the proper name justification with Ethicon.
Trans-BLA Group: No
Related STNs: None
Related PMCs: None
The purpose of this external call with Ethicon, Inc. was to discuss the clinical trials (section 6.1) included in the Adverse Reactions (AR) section of the Package Insert (PI).
FDA requested a revised Adverse Reactions table (i.e. table 1 for section 6.1 of the EVARREST package insert). Specifically on Friday, September 21, 2012 FDA requested that Ethicon provide adverse reaction event rates for the Adverse Reactions table 1 in the current draft of the EVARREST package insert, which is dated September 19, 2012. FDA noted that the response provided by Ethicon on September 23 via email communication (see appendix 1) was not sufficient:
The event rates for the adverse reactions identified in table 1 section 6 Adverse Reactions of the current PI need to be inserted. Also additional text stating what safety population was used to derive the denominator is need. For example, if Ethicon proposes to include the safety information from the safety database for which EVARREST was used as an adjunct to hemostasis, then the denominator would be 239. If they propose to use only the major studies included in the integrated safety summary set, the denominator would be 229.
Ethicon stated that they derived the adverse reactions by using “causality” and the incidence (number of adverse reactions). FDA stated that adverse reactions can include class adverse reactions not just those seen with EVARREST. Ethicon stated that they were following the regulations for reporting of adverse reactions in the package insert.
Ethicon expressed understanding of FDA’s request an agreed to provide the information as soon as possible. FDA stated that the action due date is very close so the sooner the information is sent the better because the label is still under review and there are outstanding items for the PI which have not been mutually agreed upon. Ethicon stated that they would probably able to get the information to FDA by September 25, 2012.
Dear Dr. Lindsey/Tracy,
Section 6 of the Prescribing Information originally summarized the adverse events occurring during clinical studies. However, following FDA’s request to present only adverse reactions, this was revised to show all events assessed as potentially related to the product during all clinical trials (i.e. in the entire safety database).
Please find below the detailed information to support Table 1 of the Prescribing Information.
ISS Table 3.1.1 (from the Complete Response Letter response) shows that there were 11 subjects who experienced potentially related events (‘adverse reactions’) in the three Phase 3 clinical studies (400-07-002, 400-08-002 and 400-10-001). Additionally of the 14 subjects treated in the Phase I and Phase II studies, one potentially related event of post-operative bleeding was reported.
Number of subjects experiencing any during/post treatment AE by category
Safety analysis set
________FP All_________ ________Control________
Category (n=229) (n=107)
Individual AE (^) Yes 1771 ( na ) 1038 ( na )
Individual SAE (^) Yes 121 ( na ) 55 ( na )
At least 1 ($) Yes 219 ( 95.6%) 102 ( 95.3%)
Serious ($) Yes 71 ( 31.0%) 35 ( 32.7%)
Severe ($) Yes 50 ( 21.8%) 25 ( 23.4%)
Action taken (%$) Yes 212 ( 92.6%) 96 ( 89.7%)
Death ($) Yes 10 ( 4.4%) 4 ( 3.7%)
Related to product (+$) Yes 11 ( 4.8%) 3 ( 2.8%)
Rebleed ($) Yes 4 ( 1.7%) 4 ( 3.7%)
Thrombotic ($) Yes 8 ( 3.5%) 4 ( 3.7%)
Transfusion related ($) Yes 0 ( 0.0%) 0 ( 0.0%)
This makes a total safety database of 229 + 14 = 243 subjects and a total of 11 + 1 = 12 subjects experiencing adverse reactions.
The potentially related events (adverse reactions) are listed by preferred term in the clinical study reports (Study 400-07-002 Text Table 24 AEs with Potential Causal Relationship to Study Treatment (Safety Set), Study 400-08-002 Text Table 27 AEs with Potential Causal Relationship to Study Treatment (Safety Set), Study 400-10-001 Text Table 29 AEs with Potential Causal Relationship to Study Treatment (Safety Set) and Study –b(4)--------- These information were used to compile Table 1 within the PI. In some cases the investigator’s verbatim term was used in the CSR tables, but for consistency, in compiling Table 1 for the PI, the preferred terms and SOC given in the listings were used.
One event (increased blood fibrinogen) occurred in 3 subjects, post procedural hemorrhage occurred in 2 subjects and each other event in the table occurred in 1 subject only. The total number of events (by preferred term) in the table is 12, but some subjects experienced more than one reaction (i.e. more than one preferred term).