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Vaccines, Blood & Biologics

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Summary Basis for Regulatory Actions, February 19, 2013 - Isoplate Solution

Date:  February 19, 2013

From:  Jan Simak Ph.D., Chair of the Review Committee

NDA#:  BN090067

Applicant Name:  B. Braun Medical, Inc.

Date of Submission:  January 7, 2013

PDUFA Goal Date:  March 5, 2013

Proprietary Name/ Established Name: Isoplate Solution in the 500mL EXCEL® container

Indication:  Isoplate™ Solution Platelet Additive Solution [PAS-F] is an isotonic solution to replace a portion of the plasma to store Platelet Pheresis, Leukocytes Reduced PAS products collected using a hyperconcentrated collection on Terumo BCT’s Trima Accel® System. The solution should never be infused directly to the patient. Platelet Pheresis, Leukocytes Reduced Platelet Additive Solution [PAS] products are stored in a mix of 65% Isoplate™ and 35% plasma. Platelets in Isoplate™ Solution can be stored at a concentration range of 700-2100 x 106/mL for up to 5 days at 20-24°C with continuous agitation in the EXCEL® container.

 

 Recommended Action:  Approval  

Signatory Authorities Action:
Office Signatory Authority:  Jay S. Epstein, MD, Director, OBRR _____________
□ I concur with the summary review.
I concur with the summary review and include a separate review to add further analysis.
I do not concur with the summary review and include a separate review.

Material Reviewed/ Consulted        Specific documentation used in developing the SBRA    Reviewer Name – Document(s) Date

Clinical Review

Jan Simak, CBER/OBRR/DH/LCH – Feb 19, 2013

Clinical Pharmacology Review

N/A

Labeling  Review

Lore Fields, CBER/OBRR/DBA – Feb 13, 2013

Statistical Review

Chinying Wang, CBER/OBE – May 4, 2012

CMC Review

Minerva Hughes (CDER) – Feb  24, 2012

Pharmacology/ Toxicology Review

Jolanda Branch, CBER/OBRR/DH – Feb  8, 2012  

Biomonitoring Review

Anthony Hopkins, CBER/OCBQ – March 12, 2012

Establishment Review

Nawab Siddiqui, CBER/OCBQ – March 8, 2012

Advisory Committee Transcript

N/A

Proprietary Name Review

Dana Martin, OCBQ/DCM/APLB -  Jan 29, 2013

Epidemiology Review

Faith Barash, CBER/OBE – Apr 9, 2012

1. Introduction

This summary basis of regulatory action (SBRA) pertains to a new drug application for a novel platelet additive solution Isoplate Solution in the 500 mL EXCEL® container to be used for the storage of Trima Accel leukoreduced apheresis platelets.

This document will cover the disciplines of Chemistry Manufacturing and Controls (CMC), Toxicology, Clinical and Statistical aspects, Establishment review, Biomonitoring, and Proprietary name review.

2. Background

Platelet transfusion products are procured from donors either by preparation from a whole blood donation or through an automated apheresis procedure. Currently in the U.S. platelets for transfusion, after their collection, are stored in the plasma of donors or in a newly approved platelet additive solutions (PAS)  InterSol® (Fenwal; BN080041). In the last 25 years, alternate storage solutions with a range of plasma concentrations have been proposed. In 1995 Plasma Additive Solution (PAS) II was the first solution used in European blood centers to store pooled buffy coat platelet products. PAS II contains acetate as a nutrient for the platelets, citrate to prevent clumping and activation, and sodium chloride for osmolarity.  InterSol® is similar to PAS II with the addition of phosphate. The InterSol® formulation is currently used in Europe as a processing solution in the pathogen inactivation process INTERCEPT Blood system for platelets. The InterSol® has also been approved in a number of European countries as a stand alone configuration (i.e. independent of pathogen reduction) for the storage of platelets in a fixed mixture ratio with plasma. Composition of the new PAS Isoplate (PAS-F) submitted in this NDA is different from Intersol, containing additional components including potassium, magnesium and gluconate. Both Intersol and Isoplate do not contain D-glucose and therefore there are used to replace just 65% of plasma.  The residual 35% of plasma are essential source of energy for the stored platelets. This submission pertains only to leukoreduced apheresis platelets collected by Trima Acce1 system (Terumo BCT). The NDA approval is linked to the recent 510(k) clearance of  BK120049 Trima Acce1 System (Version 6.2) for the collection of hyperconcentrated platelets.

3. Chemistry Manufacturing and Controls (CMC)

 a) Product Quality

The Chemistry, manufacturing and control (CMC) section of this application was reviewed by both CDER Office of New Drugs Quality Assessment as a consult review for all CMC sections.

  1. CMC

 The Isoplate Solution is identical to the Isolyte® S, pH 7.4 (Multi-Electrolyte Injection) an FDA approved sterile, nonpyrogenic intravenous injection packaged in B. Braun’s EXCEL® Container. The Isolyte® S, pH 7.4 is 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.

ISOPLATE  (B.BRAUN) PAS Composition
Each 100 mL contains:
Dibasic Sodium Phosphate, Heptahydrate, USP                     12 mg
Monobasic Potassium Phosphate, NF                                                    0.82 mg                  
Sodium Acetate, Trihydrate, USP                                          370 mg
Sodium Chloride, USP                                                           530 mg
Potasium Chloride, USP                                                         37 mg
Magnesiun Chloride, Hexahydrate, USP                                 30 mg
Sodium Gluconate, USP                                                           50 mg
Water for injection                                                                    qs
NaOH, Glacial Acetic Acid                                                       pH adjustment

Each drug substance manufacturer included appropriate statements of compliance with applicable guidelines and regulations for safety.
Considering previously approved ANDA 19-696 for identical product, new NDA 090067 provided sufficient information to assure the identity, strength, purity, and quality of the drug product. Therefore, the NDA is recommended for approval from the chemistry, manufacturing, and controls perspective.

b) CBER Lot Release

CBER lot release does not apply since the Isoplate Solution  in the 500 mL EXCEL® container is not a biological material.

c) Facilities review/inspection

The Isoplate Solution is identical in formulation, packaging, sterilization, and manufacturing as B. Braun’s already approved Isolyte S, pH 7.4 (Multi-Electrolyte Injection), ANDA 019696. The only difference between the Isoplate product and the approved Isolyte S, pH 7.4 (Multi-Electrolyte Injection) product is the indication. The manufacturing facility located at Irvine California was inspected last on February 23-March 5, 2009.

B. Braun Medical Inc.
2525 McGaw Avenue
Irvine, CA 92614
FEI: 2021236
Date of Last FDA Inspection: February 23-March5, 2009

OCBQ/DMPQ  CBER recommended approval and issued the Categorical Exclusion memo.

 d) Environmental Assessment

No adverse impact is expected on animals, plants, humans, other organisms, or ecosystems.

4. Nonclinical Pharmacology/Toxicology

Toxicology studies of the Isoplate (Isolyte) solution itself were assessed as a part  ANDA 019696 and found acceptable. 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  container  closure  system  used  in  manufacturing the  FDA  approved  product  Isolyte  is identical to that used in the Isoplate Solution product.   The analysis of the material used to manufacture the Excel® plastic container was performed in ---(b)(4)----:
•   --------------(b)(4)---------------------------------------------------------------------------.
•   --------------(b)(4)--------------------------------------------------------------------------.
•   ---------------(b)(4)--------------------------------------------------------------------------.
 

All information related to the container closure system presented in this NDA has already been approved for use by the Agency and is currently used in approximately 29 approved products. The complete description of the testing and the results are provided in B. Braun’s DMF (b)(4), Material Qualification for the Excel® Plastic Container, submitted to the FDA on June 30, 1986.

5. Clinical Pharmacology

N/A as the drug has no inherent pharmacological effect.

6. Clinical/ Statistical

a) Clinical Program

Prior to the submission of this NDA FDA had reviewed and approved the study protocols under IND 13684.

Efficacy studies consisted of in vitro testing and in vivo radiolabeling studies.
 

  1. In vivo radiolabeling studies for 5-day test platelets

In recovery and survival studies of radiolabeled platelets as compared to “fresh” radiolabeled control platelet samples drawn and prepared on day of reinfusion of test samples the 5-day test product showed successful results for both recovery and survival. Success criteria are Test/Control ratio: > 66% for recovery, and > 58% for survival. These criteria are satisfied if the upper limit of a two-sided 95% confidence interval of the mean percent recovery of (0.66 Control – Test) is < 0 and the upper limit of a two-sided 95% confidence of the mean percent survival of (0.58 Control – Test) is < 0. For the test product the mean recovery ratio was 88% and the mean survival ratio was 79%.

  1. In vitro results

All parameters, except for pH, were compared to a concurrent control (platelets stored in plasma). A relative difference of less than 20% between test and control for each of these parameters is deemed not clinically relevant. A difference of > 20% in some in vitro parameters may be clinically meaningful.  A non-inferiority statistical approach was used to assess the 20% difference.

For in vitro testing the control consisted of an apheresis platelet product collected from the same donor (paired control) and stored in 100% plasma.

    1. pH (primary parameter):  success criterion for pH is > 6.2 for 95% of the products with 95% confidence.  All 66 test products in the study met the FDA criteria.
       
    2. Of the remaining in vitro test parameters, the in vitro Isoplate stored platelet quality study failed in one secondary endpoint, the surface P-selectin expression, which was more than 20% higher in the test group (22± 15.4 %) compared to control (15.1± 9.1%). The high P-selectin expression (> 20% higher compared to control) on 5 day Isoplate stored platelets is a significant finding that may have clinical consequences. Similar finding of elevated P-selectin expression were observed in the Intersol stored platelets and PMR was issued for the Intersol product.  To assure clinical safety of the product, a postmarket study focused on platelet transfusion adverse events will be required in the same extent as required for Intersol.

Review of the available European hemovigilance data for Intersol stored platelets (Transfusion Clinique et Biologique 2007: 100-106; Transfusion Clinique et Biologique 2008: 289-293; French annual hemovigilance report 2008) and randomized studies (Transfusion 2000; 40:398-403; Blood 2006; 108:3210-3215) on the use of either InterSol or other similar platelet additive solutions for storage of platelets revealed no alarming findings that would preclude approval of the product. Nevertheless, post marketing studies were considered necessary to track adverse events in the recipients.

      Conclusions:

Efficacy: Demonstrated by successful outcomes in the primary parameters of pH, in vivo recovery and in vivo survival.

Safety: Platelets stored in similar additive solution Intersol and transfused to patients raised no undue safety concerns.

In order to further track adverse events in the recipients of  Trima Accel platelets stored in 65% Isoplate/ 35% plasma, B. Braun on behalf of Terumo BCT committed to conduct a controlled postmarketing study (PMR) pursuant to Section 505(o) of the Federal Food, Drug, and Cosmetic Act (FDCA) and consistent with the July 2009 FDA Guidance “Postmarketing Studies and Clinical Trials—Implementation of Section 505 (o) of the FD&C Act.”   Adverse events, i.e. transfusion reactions, will be captured through retrospective surveillance of the test and the control products. Transfusion reactions will be classified and compared by type (e.g. TRALI, febrile non-hemolytic transfusion reaction, allergic reaction, etc…). Terumo BCT will conduct the postmarketing requirement at selected institutions that are currently transfusing Trima Accel platelets in plasma and are planning to switch to Trima Accel Isoplate platelets.

The study protocol and statistical plan including hypothesis testing has been submitted  as an Amendment 17 of this NDA and will be further modified to achieve harmonization with the recently finalized PMR study protocol for the Intersol stored platelets.  B. Braun  on behalf of Terumo BCT commits to begin the PMR study within 3 months of FDA approval of the final protocol. The study including 12,000 transfusion is expected to take 6 years to complete and tha final report will be submitted within 6 months after completing the study (Am. 22).

  1. Biomonitoring

The bioresearch monitoring inspections of the three clinical sites did not reveal problems that could impact the data submitted in the application.

             b) Pediatrics

This application 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. 

   c) Other Special Populations

N/A

d) Overall Comparability Assessment

The Isoplate Solution is identical to the Isolyte® S, pH 7.4 (Multi-Electrolyte Injection) an FDA approved sterile, nonpyrogenic intravenous injection packaged in B. Braun’s EXCEL® Container. The Isolyte® S, pH 7.4 is approved, as of September 29, 1989 (ANDA 19-696).The preclinical data obtained as a part of ANDA 19-696 reveal no toxicological or biocompatibility concerns. Clinical data demonstrate the efficacy of platelets stored in the Isoplate. Results of an in vitro test indicating increase in platelet activation are similar to that of previously approved Intersol PAS (BN080041). These in vitro findings prompt FDA to require post marketing studies for both Intersol and Isoplate to assess adverse events in the recipients.  

7. Safety

Toxicology studies conducted on the Isoplate/Isolyte solution itself and biocompatibility testing of the leachables/extractables plastic materials from its container bag were assessed and found acceptable. Evaluation of available European hemovigilance data (Transfusion Clinique et Biologique 2007: 100-106; Transfusion Clinique et Biologique 2008: 289-293; French annual hemovigilance report 2008) and randomized studies (Transfusion 2000;40:398-403; Blood 2006;108:3210-3215) on the use of similar platelet additive solutions (Intersol) for the storage of platelets revealed no alarming safety issues.

8. Advisory Committee Meeting

OBRR reviewed information from this application and determined that referral to the Blood Products Advisory Committee (BPAC) prior to licensure was not needed for the following reasons (FDAAA [HR 3580-138 SEC. 918]: REFERRAL TO ADVISORY COMMITTEE):

  • The Isoplate Solution is identical to the Isolyte® S, pH 7.4 (Multi-Electrolyte Injection) an FDA approved sterile, nonpyrogenic intravenous injection packaged in B. Braun’s EXCEL® Container. The Isolyte® S, pH 7.4 is approved, as of September 29, 1989 (ANDA 19-696).
  • The study design to evaluate efficacy of Isoplate  was adequate and the results of the study supports the storage of Trima Accel apheresis platelets in a mixture of 65% Isoplate/35% plasma for up to 5 days.
  • Both  platelets stored in Isoplate PAS and platelets stored in a similar PAS Intersol showed significantly elevated surface expression of the platelet activation marker P-selectin. The use of  InterSol as a stand-alone platelet additive solution has been approved in Europe since 2007. European hemovigilance data revealed no alarming safety issues for the Intersol stored platelets. Therefore no serious safety issues are expected with clinical use of the Isoplate stored platelets. Potential effect(s) of increased platelet activation on the rate of adverse events with clinical use of the Isoplate stored platelets will be investigated in the required postmarket study.
  • BPAC discussion of this application is unlikely to change the outcome of the review of this file from a regulatory standpoint.

9. Other Relevant Regulatory Issues

N/A
 

10. Labeling

Final labeling of the package insert and directions for use reflects the experimental conditions and the outcome of the clinical studies. The labeling is acceptable .

A Proprietary Name Review was conducted by Advertising, Promotional, and Labeling Branch(APLB). APLB recommended that the proposed proprietary name, Isoplate Solution in the 500mL EXCEL® container, be found acceptable.

11. Recommendations and Risk/ Benefit Assessment

a) Recommended Regulatory Action

The recommendation is for the approval of this NDA with a post marketing requirement to conduct a controlled study to track the adverse events in the recipients.

b) Risk/ Benefit Assessment

The clinical studies described above revealed that one of the secondary endpoint of in vitro study failed to meet the FDA acceptance criteria. The platelet surface expression of P-selectin (CD62) was significantly increased (> 20% higher compared to control) in Isoplate stored platelets compared to the control. This finding indicates increased activation of Isoplate stored platelets that may have clinical consequences. Similar finding of elevated P-selectin expression was observed in the Intersol stored platelets and PMR was issued for the Intersol product.  To assure clinical safety of the product, a postmarket study focused on platelet transfusion adverse events will be required in the same extent as required for Intersol.  The NDA approval is recommended since available European data on the use of  a similar PAS InterSol or other similar platelet additive solutions for the storage of platelets raised no undue safety concerns (Transfusion Clinique et Biologique 2007: 100-106; Transfusion Clinique et Biologique 2008: 289-293; French annual hemovigilance report 2008; Transfusion 2000;40:398-403; Blood 2006;108:3210-3215).

c) Recommendation for Postmarketing Risk Management Activities

N/A

d) Recommendation for Postmarketing Activities.

The approval letter includes a post marketing requirement for the sponsor to conduct a controlled study to track the adverse event rate in the recipients.