Record of Telephone Conversation - Wilate, August 11, 2009


System Info - 102990  COTTRELL, PAULINE   21-Aug-2009 14:53:54  COTTRELL

RECORD OF TELEPHONE CONVERSATION

Submission Type: Original Application   Submission ID:  125251/0    Office: OBRR  

Product:

Coagulation Factor VIII/von Willebrand Factor Complex (Human) [Wilate]

Applicant:                                                                       

Octapharma Pharmazeutika Produktionsges.m.b.H.          

Telecon Date/Time:  11 August 2009, 08:30 – 09:30 A.M.      Initiated by FDA?  Yes

Telephone Number:    

Communication Category(s):

1. Advice

2. Information Request

Author:  PAULINE COTTRELL

Telecon Summary:  Discussion of Potency Assay: VWF:RCo

FDA Participants:  Pauline Cottrell, Timothy Lee and Donald Lebel

Non-FDA Participants:   

Stanley Ammons, Barbara Rangetiner ,Xenia Serro ,Sigurd Knaub, Bruce Schwartz, Josef Weinberger, Christian Haderer , Gerda Wiry, Tor-Einar Svae, Gerhard Gruber
Telecon Body:

FDA requested a telecon to discuss the VWF:RCo Activity Assay to further clarify the Standard Operating Procedure (SOP) for Octapharma’s VWF:RCo assay.
•Mr. Lebel asked if the lots that were submitted earlier for testing were consecutive lots.  Octapharma said they were not.
•Mr. Lebel asked what standards were used during testing.  Octapharma said that the primary standard was used to determine the vonWillebrand Factor (VWF) concentration in the in-house standard, and then the in-house standard was used for routine testing.
•Mr.Lebelasked which standard was used to determine potency of the manufactured lots, the WHO 00/514(1st International Standard for VWF Concentrate) or Octapharma’s in-house standard Lot ------(b)(4)--------, which is calibrated against the WHO standard.  Octapharma explained that for validation of the BCS assay, the WHO standard was used to calibrate the in-house standard, and the in-house standard was used for routine lot release testing.
•Mr. Lebel asked what SOP was used to determine the potency of the in-house standard - the modified assay or the standard assay.  Octapharma explained that the modified assay was used to determine the in-house standard potency value.  A BCS (Behring Coagulation System) instrument was used for this assay.  Since Behring was purchased by Siemens, the BCS Assay is now called the Blood Coagulation System.  They further explained that in routine testing, their in-house standard was used, which had been calibrated against the WHO VWF Concentrate standard and are viewed to be comparable standards and therefore were used interchangeably.  In the event of a problem with the in-house standard, Octapharma said they used the WHO standard to determine the potency.  FDA responded that it is not clear which assay is being used at any given time.  And, in the submission, it was not clear which method, i.e., the standard BCS method or the modified BCS method, was used to determine potency.  FDA also mentioned that standards should not be used interchangeably.  The standard needs to be specified in the SOP, and used all of the time for lot release.
•Dr.Lee further indicated that including the initial manual method, there are three different assay methods for potency determination, and these methods produce different VWF:RCo results for a given sample.  For example, Lot # ----(b)(4)---- has a potency value of 84 IU/mL by the manual method, and 119 IU/mL by the modified BCS method.  Since most of the laboratories outside of Octapharma do not use the modified BCS method, how does Octapharma plan to reconcile between different labs when comparing Octapharma’s values with those of other labs?  Octapharma explained that due to the nature of the product, they are still discussing how to correlate between their values and values from other testing labs outside of Octapharma.  Due to the variability of the VWF:RCo assay, Octapharma developed the modified assay and used this assay to evaluate the PK data along with the standard BCS assay.  The modified assay showed better sensitivity and correlation.
•Mr. Lebel wanted to know the concentration of ristocetin in the BCS von Willebrand reagent, if known.  Octapharma indicated that they did not have that information available at the telecon.  They indicated that when they used the aggregometer for the VWF:RCo assay, they did not observe any difference in values when they --(b)(4)--- -------------------------------------- in the assay.  However, the ---(b)(4)-- ----------------------------------------seemed to improve the sensitivity of the BCS method.
•Dr. Lee explained that FDA is struggling to correlate Octapharma’s assay values with those of other established labs.  The FDA lab is trying to verify Octapharma’s assigned VWF:RCo results in order that they can be used to label the Wilate product.
•Dr. Lee said that the PK data will determine how the product will be dosed.  FDA said that a determination needs to be made shortly as to which set of data is to be used for product release and PK parameters.
•Mr. Lebel stated that the terminology used in the SOP is not consistent.  As a result, it is not clear as to which test method and standard were used for various samples to determine their potency.  Octapharma said that they have 2 reference standards, one for patient plasma and one for concentrate, and both are used in the modified BCS assay.  Octapharma will resubmit their revised SOP and use one name consistently.
•FDA said that the use of the BCS assay for lot release is not a problem but the use of the modified assay may be since not many labs use it.  There needs to be some correlation between the two assays. 
•---------(b)(4) 
•FDA asked that additional Wilate lots be submitted to the FDA as soon as they are available.  Dr. Lee explained that since the original application was submitted in 2006, the conformance lots would have been either expired or close to expiry.  Therefore, more recently manufactured lots should be submitted along with the revised testing protocol used for manufacture.  Mr. Lebel informed Octapharma to send them to the same address.  These vials should also be labeled as Octapharma would for distribution in the United States so that they will be able to meet the FDA requirements in the lot release testing program.  Mr. Lebel also indicated that 5 vials of each lot with a mixture of both dosage strengths should be submitted.
•Dr.Leeasked if there were any modifications to the Factor VIII (FVIII) assay and it is still the --------(b)(4)------- assay.  Octapharma said that no changes were made to the FVIII assay but they use the chromogenic assay that was agreed upon in 1997.
•Octapharma clarified that the Blood Coagulation System and the Behring Coagulation System are the same, and when referenced, they are referring to their modified BCS assay.  FDA again strongly urged Octapharma to be consistent in their naming of assays throughout their SOP and submission.
•Ms. Cottrell asked about FDA’s request for the Pharmacovigilance plan.  Octapharma said they had received FDA’s email and will be able to respond in the requested time frame, i.e., by August 26, 2009.

Action Items:
•Octapharma will send a revised SOP with clarifications and consistent terminologies throughout their protocol.
•Octapharma will send their conformance lots as soon as they are available, probably by October 2009.

End
