
BN090067 Review Memo - Isoplate Solution

 

 
From:              Lore Fields MT(ASCP)SBB, OBRR/DBA/BPB

Applicant        B Braun

Subject:          BN090067

To:         Iliana Valencia, RPM/DBA/OBRR

                        Jan Simak, LCH/DH/OBRR Scientific Lead
                                                            
Through:        Leslie Holness, M.D., BPB Chief, Division of Blood Applications

Background:

This is NDA for a platelet additive solution Isoplate manufactured by B Braun.  This solution is under study to be used in conjunction with the Trima Accel instrument.     This solution was approved by CDER under ANDA 19-696 in 1989 as Isolyte S, pH 7.4 (Multi-Electrolyte Injection).  The solution is being submitted again to change the indications for use statement.

The firm submitted the same data they submitted to CDER and this will be evaluated by other parts of the review team. In addition, there are multiple studies being performed with Cariadian BCT Trima Accel collected Platelet Pheresis, Leukocytes Reduced under IND and IDE for both in vitro and in vivo platelet quality studies that are being evaluated by LCH. 

The BPB review is of the labeling submitted and a few general comments on the studies submitted in support of the platelet storage solution.

Review:

Protocol III: Invivo Platelet Study:  Subject -(b)(6)- was excluded due to low pH (5.9) at day 5 of storage.  It was also reported that severe platelet clumping was observed on the day of collection.  The investigation of this donor with a normal collected product (100% Plasma storage) showed no evidence of clumping or low pH at day 5.  This donor was excluded.  The firm stated that low pH is a cause of bad results when performing radio labeling studies.  I agree that the product should not have bee transfused however, I am not sure that the firm provided any solid evidence as to cause for the following reasons:
•The platelet product stored with plasma was collected on a -(b)(4)- instrument and not using a Trima Accel  hyperconcentrated procedure.  We should be concerned as hyperconcentrated Trima Accel products have had issues in the past.  The firm should perform a hyperconcentrated procedure before exclusion.
•The donor and product evaluation forms completed at Yale do not indicate that the product was clumping and all of the platelet counts were in normal concentrations.  The firm should clarify where this information was documented and provide those documents.
•The test reports on the product indicate that the pH was <6.8.  There are no results for a pH of 5.9.  The firm should provide the test result for the low pH value.

The firm should provide the appropriate information and documentation to justify the exclusion.

Labeling:

Package Inset:
1.The labeling should include the ISBT name for product labeling.  The firm should revise the labeling to include the ISBT approved name.  Example:   Isoplate Solution (next line) Platelet Additive Solution [Insert designation]
2.The firm has use the following indication for use statement :  INDICATIONS AND USAGE:  Isoplate Solution is indicated as a platelet additive solution for the storage of leukoreduced hyperconcentrated apheresis platelets collected on CaridianBCT’s Trima Accel® System under standard blood banking conditions. The firm should revise the indications and Usage statement to the following: 

            INDICATIONS AND USAGE:  
Isoplate Solution 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 CaridianBCT’s Trima Accel® System.  The solution should never be infused directly to the patient.

Platelet Pheresis, Leukocytes Reduced Platelet Additive Solution [Insert designation] products are stored in a mix of 65% Isoplate and 35% plasma. Platelets in Isoplate Solution can be stored at a concentration range of (b)(4)-2100 x 106/mL for up to 5 days at 20-24°C with continuous agitation in the [Insert storage bag] container.
3.The firm has the following under dosage and administration: DOSAGE AND ADMINISTRATION Leukoreduced apheresis platelets are stored in a mix of 65% Isoplate Solution and 35% plasma. Platelets in Isoplate Solution can be stored at a concentration range of (b)(4)-2100 x 106/mL for up to 5 days at 20-24°C with agitation.  The firm should revise the statement to read:

Dosage and Administration:
Isoplate Solution may only be used with the Trima Accel automated blood cell separator device.  For full instructions on the use of Isoplate Solution with the Trima Accel see the Trima Accel Operator’s Manual.
[Insert directions on how to connect the solution to the Trima kit]
4.Contraindications:  The labeling for the drug approved in CDER under the ANDA has several warnings on usage with certain patient populations.  The firm should clarify why those warnings have not been included in this package insert or supply studies that have changed the warnings.
5.   Warnings and precautions:  The firm states that the solution is not for direct intravenous infusion.  The firm should revise the statement since the solution will be directly infused with the platelet product.
6.   The firm has the following statement in the Adverse Reactions section:  Isoplate Solution is added to leukoreduced hyperconcentrated platelets after the Trima Accel apheresis procedure is complete. It is not for direct intravenous infusion. Isoplate Solution is not expected to cause adverse events other than those normally associated with platelet transfusion.  The firm should revise the statement to:  Isoplate Solution is added to Platelet Pheresis, Leukocytes Reduced PAS products collected using a hyperconcentrated Trima Accel apheresis procedure after completion. It is not for direct intravenous infusion. Isoplate Solution is not expected to cause adverse events other than those normally associated with platelet transfusion.
7.Clinical Trials Experience:  The firm states the results of the radio label study under this section.  I think this is misleading as the drug was not actually transfused with the platelet and was in a much smaller dosage than intended.  The firm should revise this section to not include clinical trials as none were performed.
8.The firm has the following language in the description: Isoplate Solution is indicated as a platelet additive solution for the storage of hyperconcentrated leukoreduced apheresis platelets collected on CaridianBCT’s Trima Accel® System under standard blood banking conditions. This should be revised to: Isoplate Solution is indicated as a platelet additive solution for the 5 day storage of Platelet Pheresis, Leukocytes Reduced PAS products collected using a hyperconcentrated collection on CaridianBCT’s Trima Accel® System.  Platelets in Isoplate Solution can be stored at a concentration range of (b)(4)-2100 x 106/mL for up to 5 days at 20-24°C with agitation.
9.Clinical Studies, In Vivo Study:  The firm states: A paired study was completed to verify that in vivo radiolabeled recovery and survival of hyperconcentrated platelets collected on the Trima Accel System, diluted in Isoplate Solution, and stored for five days (Test) meet FDA acceptance criteria in comparison with fresh autologous platelets (Control). The firm should revise the statement to include that the products are leukocytes reduced.
10.Clinical Studies, In Vitro Study: The firm states: A paired study was completed to verify that in vitro platelet quality (functional assays) of hyperconcentrated platelets collected on the Trima Accel System, diluted in Isoplate Solution, and stored for five days (Test) meet FDA acceptance criteria in comparison to plasma-stored platelets (Control).  The firm should revise the statement to include that the products are leukocytes reduced.

Container Label:
11.The labeling should include the ISBT name for product labeling.  The firm should revise the labeling to include the ISBT approved name. 

Recommendations:  
I recommend that the above issue be resolved prior to approval.

Letter Ready Comments:  

Protocol III: Invivo Platelet Study:  Subject (b)(6) was excluded due to low pH (5.9) at day 5 of storage.  It was also reported that severe platelet clumping was observed on the day of collection.  The investigation of this donor with a normal collected product (100% Plasma storage) showed no evidence of clumping or low pH at day 5.  This donor was excluded.  You stated that low pH is a cause of bad results when performing radio labeling studies.  We agree that the product should not have been transfused however, we are not sure that you provided any solid evidence as to cause for the following reasons:
•The platelet product stored with plasma was collected on a (b)(4)- instrument and not using a Trima Accel hyperconcentrated procedure. You should perform a hyperconcentrated procedure before exclusion.
•The donor and product evaluation forms completed at Yale do not indicate that the product was clumping and all of the platelet counts were in normal concentrations.  Please clarify where this information was documented and provide those documents.
•The test reports on the product indicate that the pH was <6.8.  There are no results for a pH of 5.9.  Please provide the test result for the low pH value.

You should provide the appropriate information and documentation to justify the exclusion.

Labeling:

Package Inset:
1.The labeling should include the ISBT name for product labeling.  Please revise the labeling to include the ISBT approved name.  Example:   Isoplate Solution (next line) Platelet Additive Solution [Insert designation]
2.You have used the following indication for use statement :  INDICATIONS AND USAGE:  Isoplate Solution is indicated as a platelet additive solution for the storage of leukoreduced hyperconcentrated apheresis platelets collected on CaridianBCT’s Trima Accel® System under standard blood banking conditions. Please revise the indications and Usage statement to the following: 

            INDICATIONS AND USAGE:  
Isoplate Solution 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 CaridianBCT’s Trima Accel® System.  The solution should never be infused directly to the patient. 
Platelet Pheresis, Leukocytes Reduced Platelet Additive Solution [Insert designation] products are stored in a mix of 65% Isoplate and 35% plasma. Platelets in Isoplate Solution can be stored at a concentration range of (b)(4)-2100 x 106/mL for up to 5 days at 20-24°C with continuous agitation in the [Insert storage bag] container.
3.You have the following under dosage and administration: DOSAGE AND ADMINISTRATION Leukoreduced apheresis platelets are stored in a mix of 65% Isoplate Solution and 35% plasma. Platelets in Isoplate Solution can be stored at a concentration range of (b)(4)-2100 x 106/mL for up to 5 days at 20-24°C with agitation.  Please revise the statement to read:

Dosage and Administration:
Isoplate Solution may only be used with the Trima Accel automated blood cell separator device.  For full instructions on the use of Isoplate Solution with the Trima Accel see the Trima Accel Operator’s Manual.
[Insert directions on how to connect the solution to the Trima kit]
4.Contraindications:  The labeling for the drug approved in CDER under the ANDA has several warnings on usage with certain patient populations.  Please clarify why those warnings have not been included in this package insert or supply studies that have changed the warnings.
5.   You have the following statement in the Adverse Reactions section:  Isoplate Solution is added to leukoreduced hyperconcentrated platelets after the Trima Accel apheresis procedure is complete. It is not for direct intravenous infusion. Isoplate Solution is not expected to cause adverse events other than those normally associated with platelet transfusion.  Please revise the statement to:  Isoplate Solution is added to Platelet Pheresis, Leukocytes Reduced PAS products collected using a hyperconcentrated Trima Accel apheresis procedure after completion. It is not for direct intravenous infusion. Isoplate Solution is not expected to cause adverse events other than those normally associated with platelet transfusion.
6.Clinical Trials Experience:  You state the results of the radio label study under this section.  I think this is misleading as the drug was not actually transfused with the platelet and was in a much smaller dosage than intended.  Please revise this section to not include clinical trials as none were performed.
7.You have the following language in the description: Isoplate Solution is indicated as a platelet additive solution for the storage of hyperconcentrated leukoreduced apheresis platelets collected on CaridianBCT’s Trima Accel® System under standard blood banking conditions. This should be revised to: Isoplate Solution is indicated as a platelet additive solution for the 5 day storage of Platelet Pheresis, Leukocytes Reduced PAS products collected using a hyperconcentrated collection on CaridianBCT’s Trima Accel® System.  Platelets in Isoplate Solution can be stored at a concentration range of (b)(4)-2100 x 106/mL for up to 5 days at 20-24°C with agitation.
8.Clinical Studies, In Vivo Study:  You state: A paired study was completed to verify that in vivo radiolabeled recovery and survival of hyperconcentrated platelets collected on the Trima Accel System, diluted in Isoplate Solution, and stored for five days (Test) meet FDA acceptance criteria in comparison with fresh autologous platelets (Control). Please revise the statement to include that the products are leukocytes reduced.
9.Clinical Studies, In Vitro Study: You state: A paired study was completed to verify that in vitro platelet quality (functional assays) of hyperconcentrated platelets collected on the Trima Accel System, diluted in Isoplate Solution, and stored for five days (Test) meet FDA acceptance criteria in comparison to plasma-stored platelets (Control).  Please revise the statement to include that the products are leukocytes reduced.

Container Label:
10.The labeling should include the ISBT name for product labeling.  Please revise the labeling to include the ISBT approved name. 
