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Vaccines, Blood & Biologics

1/23/2008 Email - Rotarix

From: Henchal, Laraine

Sent: Wednesday, January 23, 2008 5:54 PM

To: ''

Cc: Vujcic, Luba

Subject: Request for 125265/0 Lot Testing and assay info

Hi Donna,

I have been able to get confirmation of number of vials needed for CBER testing of lots of Rotarix in support of licensure. Please send to the sample custodian (Joseph Quander III, OCBQ, DMPQ, PRB) the following:

35 vials lyophilized vaccine of each of 3 lots
5 containers diluent of each of 3 lots

Address I have is:

Nicholson Lane Research Center
5516 Nicholson Lane
Kensington, MD 20895
Ph 301-594-6517

Also, please submit the Draft Lot Release Protocol to both Joe and me (you can e-mail to me) and as an amendment to the BLA (it can be combined with other submissions).

I also have the following comments from one of our assay reviewers and it would seem that these same comments were sent to STN #----------- recently. We are sending these for STN #125265/0 to make the file complete. When you respond to the other BLA, you can simply cross reference your response for this file in an amendment (which can be combined with other submissions).

The limit of quantitation (LOQ) for ------ pneumococcal serotype is presented in Table 4 of ---------------. --------------------- LOQ is based on the -------------------- from --- assays. The ------------------- plus --- standard deviations (SD) is also provided. Please address the following:

We note that a -------- cut-off value of ---- µg/mL was implemented for the ELISA based on the following ------- elements: --------------------------------------------------------------------------------------------------------------------------------------------------------------. According to your response, the ---- µg/mL cut-off value was recommended as the LOQ for ELISAs suitable for the ----------- of pneumococcal polysaccharide antibodies by Carl Frasch, Ph.D. We find no evidence of this statement or any recommendation by Dr. Frasch. Please comment.

b. It appears that implementing the ---- µg/mL cut-off has ------------ the LOQ for ------------. The range of ----- LOQ values (--------------µg/mL) in Table 4 ------------------ cut-off value of ---- µg/mL. Moreover, the standard deviation of ------ serotype-specific LOQ indicates that ----------- supports this cut-off when assay variability (----- LOQ + -- SD) is accounted for. A similar situation was noted in the --------- assay validation report (------------). Neither the ------- of LOQ values (------------- µg/mL) nor the ----------- of ----- serotype-specific LOQ support the use of the ---- µg/mL -------- cut-off value. CBER does not recommend the establishment of a ---------- cut-off unless it is supported with data from ------ serotype. Implementing a --------- cut-off value could result in a less precise assay with values above the actual LOQ reported as < LOQ. In addition, the reporting of less precise results could increase the variability of the data overall and widen confidence limits which would decrease the power to detect differences between groups (especially individuals with low antibody levels). CBER considers the ELISA for ----- pneumococcal serotype to be a separate assay. As such, we recommend that the quantitation limit for ----- serotype-specific assay be based on the LOQ calculated --------- ----------. Please comment.

2. The pneumococcal validation report also indicates that antibody concentrations below the assay cut-off of ---- µg/mL are considered negative. Conversely, antibody concentrations above the cut-off are considered positive. According to the ------------ assay report, samples ----------------------------------------------------------------------------------- This ----, also referred to as the --------------------------, is defined as the -----------------------------µg/mL) -------------------------------------------------------------------------------------. Please address the following:

The -------- appears to be somewhat arbitrarily set at ----------- µg/mL. How was this ------ determined? Please submit all serotype-specific data in your response.

b. Please explain how all values below the -----µg/mL cut-off are considered negative when ----- LOQ values range from -------------- µg/mL.

c. Table 5 was submitted as a summary of the -------- principles for samples that fall within the --------. When a ------------------ test confirms that a sample is negative ------- µg/mL), the result is reported as ------. What is the rationale for reporting values as ------ when validation data indicate that some of these values may be above the actual LOQ?

d. Are results ----------- µg/mL cut-off given a value for trending purposes? Is variability of data below the cut-off value evaluated? If so, please submit your guidelines for assigning values and trending these data.

3. We note that the specificity results in ----------- were taken from the validation of the ---------- assays. CBER previously requested that all validation parameters be evaluated with the ---------------- format in lieu of referencing the validation of the ------------- assays. However, we agree that the format changes are unlikely to impact assay specificity. Consequently, the referenced specificity results for pediatric samples are acceptable for inclusion with -------------. -----------------------------------------------------------------------------------------------------------. In addition, ----------------------------------------------------------------------------------------------------------------------------

Please comment.



Laraine S. Henchal, MAS
Microbiologist Reviewer, Team Leader
Viral Vaccines Branch
Division of Vaccines and
Related Products Applications
Office of Vaccines Research and Review
Center for Biologics Evaluation and Research
Food and Drug Administration
Phone: 301-827-3070
Fax: 301-827-3532

Contact FDA

(800) 835-4709
(240) 402-8010
Consumer Affairs Branch (CBER)

Division of Communication and Consumer Affairs

Office of Communication, Outreach and Development

Food and Drug Administration

10903 New Hampshire Avenue

Building 71 Room 3103

Silver Spring, MD 20993-0002

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