United States Public Health Service
Center for Biologics Evaluation and Research
NIH Building 29
Phone: (301) 496-2577
FAX: (301) 402-2780
Date: Nov 8, 2010
From: Jan Simak, Ph.D.
Visiting Scientist, Laboratory of Cellular Hematology
Through: Jaroslav Vostal, M.D., Ph.D.
Chief, Laboratory of Cellular Hematology
To: Iliana Valencia
Regulatory Project Manager
Subject: Midcycle Memorandum
Submission type: NDA
Product Name: Isoplate Solution in the 500 mL EXCEL Container
Aplicant/Manufacturing Site: B. Braun Medical Inc., Irvine, CA
CBER Rec. Date: July 14, 2010
Conclusion and Recommendation:
Following comments and comments from other review team members should be communicated to the sponsor:
Letter Ready Comments:
Product Development Rationale
1) You stated in the paragraph 2.5.1. that advantages of hyperconcnetrated platelets in PAS include reduced adverse transfusion reactions, facilitated ABO- incompatible transfusions, and availability of additional plasma for other purposes. Please provide all available specific clinical data supporting first two claims.
Protocol II: In Vitro Platelet Quality Study
2) Results of Protocol II in vitro study met the primary endpoint of pH > 6.2, but failed in one secondary endpoint - the surface P-selectin expression, which is more than 20% higher in the test group (22± 15.4 %) compared to control (15.1±9.1%).
FDA believes that high P-selectin expression (> 20% higher compared to control) on 5 day Isoplate stored platelets is a significant finding that may have clinical consequences.
To assure clinical safety of the product, a postmarket study focused on platelet transfusion adverse events will be required.
3) The Individual Study Information (1.13.8) of your IND13684/27 Annual Report shows high numbers of subjects not completing the study in Protocol II , e.g. at Hoxworth site 12 subjects of 25 enrolled (48% !) did not complete the study. With such high rate of subjects not completing the study, validity of submitted results is highly compromised.
Please explain the discrepancy in the rate of subjects not completing the study between participating study sites and provide detailed justification for each individual case not completing the Protocol II.
Protocol III: In Vivo Platelet Study
4) FDA has a serious concern about validity of your results of the Protocol III In Vivo Platelet Study. In the paragraph 188.8.131.52.16.2.1 Discontinued Subjects you stated that fifteen subjects from Yale site were excluded from analysis in Protocol III: In Vivo Platelet Study. For 11 evaluated subjects at the Yale clinical site 28 subjects were enrolled, 2 of them did not meet the inclusion criteria and 15 subjects were excluded from evaluation for variety of reasons. In some cases, the justification for exclusion like “low day 5 pH for test platelets” (b)(6), “radiolabel anomalies” ----------(b)(6)-----------, or “isotope not received” (b)(6), are not acceptable. In contrast, there was no subject exclusion from analysis at the Darmouth clinical site, only 3 screen failures. Extremely high exclusion rate at the Yale clinical site is not acceptable. Dramatic difference in exclusion rate between Yale and Darmouth clinical sites demonstrates that the study was not performed at these two sites with comparable quality. In addition, exclusion of 15 subjects at the Yale site may represent a bias in statistical evaluation of results. Please explain the discrepancy in the subject exclusion rate between Darmouth and Yale clinical sites.
5) Based on the stated insufficiencies of your Protocol III In Vivo Platelet Study, with continuing concern on recovery and survival of the Isoplate stored platelets, FDA may request evaluation of CCI as a part of the required postmarked study. Background & SummaryThe Isoplate Solution is identical to the Isolyte® S, pH 7.4 (Multi-Electrolyte Injection) is a FDA approved sterile, nonpyrogenic intravenous injection packaged in B. Braun’s EXCEL® Container and approved, as of September 29, 1989 (ANDA 19-696), for the following indication: For use in adults as a source of electrolytes and water for hydration, and as an alkalinizing agent.The company performed in vitro and in vivo studies under IND 13684. So far 28 Amendments of this IND were reviewed and FDA comments communicated to the sponsor. See the review memos for IND 13684 for detailed information. The new indication of the Isolyte is as follows: Platelet additive solution for the storage of hyperconcentrated platelets. The sponsor submitted a new proprietary name of the product “Isoplate”.
Isoplate Solution Indication for Use
Indicated as a platelet additive solution for the storage of leukoreduced hyperconcentrated apheresis platelets.
The In Vivo platelet survival/recovery study of Isoplate stored platelets (Protocol III) showed satisfactory results, however, the study had extremely high exclusion rate (see the FDA comments). Based on the stated insufficiencies of your Protocol III In Vivo Platelet Study, with continuing concern on recovery and survival of the Isoplate stored platelets, FDA may request evaluation of CCI as a part of the required postmarked study.
The In Vitro platelet quality study (Protocol II) met the primary endpoint of pH > 6.2, but failed in one secondary endpoint, the surface P-selectin expression, which is more than 20% higher in the test group (22± 15.4 %) compared to control (15.1± 9.1%). We believe that high P-selectin expression (> 20% higher compared to control) on 5 day Isolyte stored platelets is a significant finding that may have clinical consequences. Therefore, we have informed the sponsor (CRMTS #7147, Sept. 9, 2009) that to assure clinical safety of the product, a postmarket study focused on platelet transfusion adverse events may be required. The Individual Study Information (1.13.8) of your IND13684/27 Annual Report shows high numbers of subjects not completing the study in Protocol II , e.g. at Hoxworth site 12 subjects of 25 enrolled (48% !) did not complete the study. With such high rate of subjects not completing the study, validity of submitted results is highly compromised.
NDA review team
Iliana Valencia (OBRR/DBA/RPMB)
Jan Simak (OBRR/DH/LCH)
Yolanda Branch (OBRR/DH/
Chinying Wang (OBE/DB/TEB)
Minerva Hughes (OPS/ONDQA/NDQAII/Branch IV)
Nawab Siddiqui (OCBQ/DMPQ/BII)
Lore Fields (OBRR/DBA/BPB)
Anthony Hopkins (OCBQ/DIS/BMB)
Faith Barash (OBE/DE/TBSB)
Catherine Miller (OCBQ/DCM/APLB)
Fileability: Yes, the application was found sufficiently complete to permit a substantive review. The review classification for this application is Standard. Therefore, the user fee goal date is April 14, 2011.
PREA: No, this application similarly to BN080041 does not trigger PREA (21 U.S.C. 355c) requirements because it does not include new active ingredients, new indications, new dosage forms, new dosing regimens, or new routes of administration. (email from Nisha Jain of 6/29/2010)
BIMO: Clinical Investigator Inspections of two sites (Drs. Dumont, Snyder) requested (8/24/2010) The Bioresearch Monitoring Branch issued inspection requests on August 24, 2010 covering two Protocol III (In vivo Platelet Study) clinical investigators and study sites: Lebanon, New Hampshire - 15 Subjects; New Haven, Connecticut - 28 subjects - inspection scheduled to begin during week of November 8-12, 2010
The above inspections are pending completion. The requested completion date for each inspection is November 22, 2010. The committee will be informed about the results of the inspections as soon as they are available (Antony Hawkins Memo 11/8/10).
DMPQ: The production facility has been recently inspected. Whether additional inspection is required will be decided by DMPQ reviewer. No outstanding DMPQ issue identified (Nawab Siddiqui email 11/8/10)
PNR: Proposed proprietary name was reviewed and found acceptable (memo from Catherine Miller of 8/11/2010)
CDER consult CMC review: Initial quality assessment performed, comments included the filing letter (memo from Minerva Hughes of 8/6/2010). Midcycle review pending.
Pharm./tox review: Comments included in the filing letter (memo from Yolanda Branch of 8/9/2010). Midcycle review pending.
Epidemiology: Midcycle review pending.
Labeling : Midcycle review pending
For both studies conducted under Protocols II and III, sponsor should provide the computed confidence intervals to determine if the acceptable criteria are met. In addition, sponsor should include the computer programs and datasets used in your analyses (Jean Wang Memo 11/5/10)
Clinical/ Scientific lead review
See the letter ready comments above.
FDA comments included in the filing letter (from CMC and pharm/tox. reviewers):
DMF letter of authorizations should reference the DMF number, the specific item being referenced, and the date of the submission for that item. Provide revised DMF letter of authorizations for the ---(b)(4)----- Sodium Chloride USP and PotassiumChloride USP drug substances. The Agency is unable to review the referenced DMFs in support of your NDA in the absence of an adequate letter of authorization.
It is noted that B. Braun Medical Inc. conducted the chemical, biological and physical functional testing on the Excel® plastic container in accordance with the USP requirements and additional B. Braun tests. The product’s proposed indication is for platelet storage in the following ratio: 65% Isoplate solution and 35% plasma. It is stated in the label that Isoplate solution will not be used for direct infusion. However, please note Isoplate will be directly infused into patients as a component of apheresis platelet products. This is of concern because there can be an accumulation of extractable/leachable beyond the acceptable range with multiple use (doses) of product. The levels of each extractable/leachable need to be assessed at the maximum daily dose of the combination product to ensure safety. Please see the comments below:a. Please note the toxicological evaluation of leachables/extractables from the plastic should be based on animal studies that defined a toxic dose of an IV administered compound and on the anticipated clinical application of the product. Please identify each extractable/leachable and calculate their levels at the maximum clinical dose, to ensure that it is within an acceptable range.
b. Please electronically submit all preclinical (toxicological) studies that are cross referenced in order to complete the file.