	  
Complete Response Letter, July 27, 2012 - Hyqvia


 
DEPARTMENT OF HEALTH & HUMAN SERVICES
 Public Health Service
 Food and Drug Administration
 1401 Rockville Pike
 Rockville, MD 20852-1448 

Our STN: BL 125402/0

Baxter Healthcare Corporation
 Attention: Angela Blackshere
 One Baxter Way
 Westlake Village, CA 91362 

Dear Ms. Blackshere:

This letter is in regard to your biologics license application (BLA) for Immune 
Globulin Infusion (Human), 10%, with Recombinant Human Hyaluronidase, 
manufactured at your Lessines, Belgium location, submitted under section 351 of 
the Public Health Service Act (42 U.S.C. 262).

We have completed our review of all the submissions you have made relating to 
this BLA. After our complete review, we have concluded that we cannot grant 
final approval because of the deficiencies outlined below. 

CLINICAL:
   Based on deficiencies identified during the FDA inspection for participating 
  sites in Study #160603, please perform a safety and efficacy analysis that 
  excludes data obtained from Study Site #1 and Study Site #11. 

PHARMACOLOGY/TOXICOLOGY:
  The submission does not contain sufficient preclinical information in relevant 
  species to assess: 
    Possible toxicity of lifetime exposure to anti-PH20 antibodies. Tissue 
    cross-reactivity studies indicate that anti-PH20 antibodies bind to the 
    enteric plexus and male reproductive tissue. The BLA does not contain 
    information on the effect of life-time exposure to these antibodies, 
    including in these tissues.
    Possible toxicity of anti-PH20 antibodies in the developing fetus and the 
    young. Transplacental transfer of anti-PH20 antibodies is expected. The BLA 
    does not contain sufficient information on possible developmental 
    immunotoxicity of the proposed product.
    Possible toxicity of anti-PH20 antibodies in pediatric patients. Pediatric 
    patients may be especially susceptible to the effect of anti-PH20 
    antibodies. The BLA does not contain information from juvenile animal 
    studies to assess the effect of anti-PH20 antibodies, especially in the 
    enteric plexus and male reproductive tissue.
    Possible effect of anti-PH20 antibodies on male and female fertility. As a 
    part of your response, please submit the complete details including a signed 
    study report, for the primate fertility study that is referenced in the 
    Halozyme study report 10059 (reference ---(b)(4)--, personal communication). 
    These details should include a description of test articles, immunization 
    details, antibody response analysis and reactivity.

LABELING:
  We reserve comment on the proposed labeling until the application is otherwise 
  acceptable. We may have comments when we see the proposed final labeling.
  Should additional information relating to the safety and effectiveness of this 
  drug product become available before our receipt of the final printed 
  labeling, revision of that labeling, may be required.

We stopped the review clock with the issuance of this letter. We will reset and 
start the review clock when we receive your complete response.

Within 10 days after the date of this letter, you should take one of the 
following actions: (1) amend the application; (2) notify us of your intent to 
file an amendment; or (3) withdraw the application. 

You may request a meeting or teleconference with us to discuss the steps 
necessary for approval. For PDUFA products please submit your meeting request as 
described in our “Guidance for Industry: Formal Meetings With Sponsors and 
Applicants for PDUFA Products,” dated February 2000. This document is available 
on the internet at 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM079744.pdf 
or may be requested from the Office of Communication, Outreach, and Development, 
at (301) 827-1800. For non-PDUFA products, please contact the regulatory project 
manager. For details, please also follow the instructions described in CBER’s 
SOPP 8101.1: Scheduling and Conduct of Regulatory Review Meetings with Sponsors 
and Applicants. This document also is available on the internet at 
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/ProceduresSOPPs/ucm079448.htm,;
or may be requested from the Office of Communication, Outreach, and Development.

Please be advised that, as stated in 21 CFR 601.3(c), if we do not receive your 
complete response within one year of the date of this letter, we may consider 
your failure to resubmit to be a request to withdraw the application. Reasonable 
requests for an extension of time in which to resubmit will be granted. However, 
failure to resubmit the application within the extended time period may also be 
considered a request for withdrawal of the application. 

If you have any questions regarding the above, please contact the Regulatory 
Project Manager, Mark Shields, at (301) 827-6173.

Sincerely yours,

Basil Golding, M.D.
 Director
 Division of Hematology
 Office of Blood Research and Review
 Center for Biologics Evaluation and Research 
 

   