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U.S. Department of Health and Human Services

Vaccines, Blood & Biologics

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Pharmacovigilance Review of Sponsor's Response to CR Letter - Spherusol

  

 

Subject:   


BLA STN 125354 CR Letter and PVP Response

 

To:      


Sheldon Morris, PhD, OVRR.

 

cc:    

 

Holly Wieland, RPM, OVRR and Jon Daugherty, PhD, OVRR

From:    

 

Alexis Mosquera, RN, OBE/DE/TBSB

 
Craig Zinderman, MD, MPH, OBE/DE/TBSB

Through     

 

David Martin, MD, MPH, Acting Chief, OBE/DE/TBSB

 
Rickey Wilson, MD, MS, JD
Director, DE, OBE
 


 
Introduction:
A complete response (CR) letter was sent to the sponsor on March 26, 2010 outlining clinical, labeling, statistical, and pharmacovigilance deficiencies in the sponsor’s BLA submission, including the lack of information for the proposed active surveillance activity for Coccidioides Immitis Spherule-Derived Skin Test Antigen (Spherusol). Note: The following review contains statements taken directly and/or indirectly from the sponsor’s response to the CR letter and the BLA submission. Paragraphs in italics were taken directly from the BLA submission.
 
Product Background
Coccidioidin SDis indicated for use in the detection of delayed type hypersensitivity (DTH) to Coccidioides immitis. A positive skin test to Coccidioidin SDindicates prior exposure to C.immitis.
Coccidioidin SDis prepared from a ----(b)(4)----- extract of C.immitis spherules.
 
However, the CR letter requested additional information on how this test will be used in a clinical setting, noting that without this description, FDA is unable to assess the risks and/or benefits of the use of this product. The sponsor’s response to the CR letter dated June 8th 2010, proposes a new indication (“Spherusol is indicated for use as a skin test antigen to detect cellular hypersensitivity to C.immitis. A positive delayed-type skin test to Spherusol can be indicative of past or present infection with C.immitis.”). Detection of active disease was not previously evaluated during the IND studies. In addition, the CR letter requested additional adverse event data that allow quantification of local and systemic reactions for each study group. *This data is pending.
 
-------------------------------------------------(b)(4)-------------------------------------------------------              ---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
 
 
Assessment of Response to CR Letter
Complete review of the pharmacovigilance plan will depend on the resolution of key clinical issues, in particular, the intended use of the product and the adverse event findings of the preapproval studies. Recommendations for optimal post-market safety monitoring require an understanding of the intended use and any safety issues identified pre-licensure. The responses to the CR letter regarding PVP items are complete, however will require clarification and negotiation if the review goes forward. Further detailed comments on some of the response items are listed below:
 
48.The objective of the survey is active surveillance for any serious adverse event. This response is complete, however the objective may need to be refined if specific safety issues are identified.

 
49.The sponsor intends to select sites for the survey that are located within endemic areas for coccidioidomycosis, depending on the number of cases seen at the site annually. The sponsor should specify the minimum number of annual cases expected for enrollment as a participating site.

 
52.Revisions to the reporting form were made as requested.  Submission of the revised form will be needed for further review.

 
53. The sponsor notes that several accepted diagnostic methods exist (serology, culture of sputum or tissue) that can confirm skin test findings. It is unclear if item # 5 on the reporting form is asking clinical sites to confirm skin test findings with one of these diagnostic methods.   The choices in item # 5 “confirm sensitivity" or "detect sensitivity” appear to be asking if the skin test was used to identify C. immitis in patients with active pulmonary disease vs. identifying past exposure to C. immitis in healthy patients. However, this interpretation was not clarified in the CR response.   Further, the use of item#5 in the survey will need additional revisions depending on the eventual indication approved for this product.