
 
  


Summary of FDA Internal Meeting, April 24, 2013 - Hyqvia


 
Our Reference: Ref. #125402/0.25
CRMTS #8779

TODAY’S DATE: April 24, 2013  

PAGES: 4 

TO: Angela Blackshere 
Baxter Healthcare Corporation  
Email address: Angela_Blackshere@baxter.com

FROM: Alpa Shah
Regulatory Project Manager 
Division of Blood Applications
Office of Blood Research and Review
Phone number: (301) 827-6122
Fax number: (301) 827-2857

SUBJECT: Summary of FDA Internal Meeting 

PRODUCT: Immune Globulin Infusion (Human), 10% with recombinant Human 
Hyaluronidase biologic license application IGIV (rHuPH20)

This meeting is being denied because the requested feedback would be best 
provided through another process.  We recommend that you respond to our 
questions of April 16, 2013, and consider these comments the official FDA 
responses to your questions.  

Questions from the Sponsor: 

Meeting request received 13-Dec-2012

8.1 Clinical

Baxter Question 8.1
Does FDA agree that the safety and efficacy re-analysis excluding Study Sites 
#1and #11 addresses the clinical item identified in the Complete Response 
letter?

FDA Response to Question 8.1
Yes.

8.2 Pharmacology/Toxicology

Baxter Question 8.2
Does the FDA agree that the additional nonclinical data, analyses and study 
designs provide sufficient information on the pharmacology/toxicology items 
identified in the Complete Response letter?

FDA Response to Question 8.2
We do not have sufficient information to determine whether the preclinical 
information you have provided is sufficient to address the possible toxicities 
of anti-PH20 antibodies.

8.3 Other 

Baxter Question 8.3
Does FDA agree on the path forward for licensure including timing for
resubmission of the BLA?

FDA Response to Question 8.3
We commit to working with you in promptly identifying what if any additional 
studies should be done to support resubmission of the BLA.

Meeting package received 27-Mar-2013

Baxter Question 10.1
The requested clinical analysis of Study 160603 excluding Sites 1 and 11 has 
been performed and Baxter has provided the evaluation of the most relevant 
parameters in this briefing document.  We conclude that there is no change in 
safety profiles or efficacy with the exclusion of these sites.  Does the Agency 
agree?

FDA Response to Question 10.1
Yes.

Pharmacology/Toxicology Questions

Baxter Question 10.2
The Complete Response Letter (CR) noted that the BLA did not contain sufficient 
preclinical information in relevant species to assess the possible toxicities of 
anti-PH20 antibodies. 

a. Does the Agency agree that the identified deficiencies have been addressed by 
the additional information/studies described?

FDA Response to Question 10.2.a
We do not have sufficient information to determine whether the preclinical 
information you have provided is sufficient to address the possible toxicities 
of anti-PH20 antibodies.

Baxter Question 10.2.b
If the Agency does not agree, please comment on what deficiencies have not been 
addressed.

FDA Response to Question 10.2 
Please refer to IR questions communicated on April 16, 2013.
  You have concluded that the originally reported detection of PH20 in enteric 
  plexus was an artifact, associated with the use of a specific rabbit anti-PH20 
  reagent.  To reach this conclusion, you performed several new studies to 
    investigate detection of PH20 in enteric plexus samples.  We will need to 
    review the details of these studies, e.g., how they were performed, reagents 
    used in each case compared to those for the original study, and what level 
    of sensitivity was achieved. 
    Emerging data (Preston et al 2012) show a role for PH20 in regulating 
    maturation of neuronal progenitor cells.  PH20 itself has been proposed as a 
    therapeutic target in MS based on its role in regulating maturation of 
    progenitor cells.  We note that your studies which failed to identify 
    neuronal PH20 expression have been performed exclusively in adult, normal 
    tissues where neuronal progenitors are expected to be few in number.  
    Expanding your data set to include evaluation of post-natal tissues and/or 
    tissues featuring tissue regeneration post-injury will make your conclusion 
    more convincing.

  Based on your conclusion that PH20 is not expressed in enteric plexus, you 
  have stated that enteric plexus considerations are not relevant for the 
  assessment of safety risk in patients with anti-PH20 antibodies.  You selected 
  species for additional preclinical studies without regard for PH20 expression 
  in enteric plexus. Please refer to IR questions communicated on April 16, 
    2013.  We are not yet convinced that PH20 is absent in enteric plexus and 
    neuronal progenitor cells. Your additional toxicology studies in rabbit may 
    be sufficient, but more information regarding the expression of PH20 in 
    enteric plexus of the rabbit is required.  If PH20 is not expressed in 
    rabbit enteric plexus, additional preclinical studies may be needed.

  We remain concerned about possible toxicities associated with lifetime use of 
  the product, particularly in juvenile populations.

Regulatory Questions 

Baxter Question 10.3.1
Does the Agency agree that Baxter can proceed with a formal response to the CR 
letter?

FDA Response to Question 10.3.1 
No, we do not agree.  
We communicated our outstanding concerns to you on April 5, 2012, and again on 
April 11, 2012.  In these communications we advised you to propose preclinical 
studies in relevant animal species, and/or clinical studies, to address the 
outstanding concerns.  Instead of sending a proposal, you have provided in this 
submission a summary of preclinical data intended to address CR item 2 
(anti-PH20 toxicity in the developing fetus and the young), and CR item 4 
(anti-PH20 toxicity in male and female fertility).  While in general the design 
of these studies appears adequate, we will need the full data set for review to 
determine if additional work will be required.  In addition, because your 
justification of the rabbit model failed to include evaluation of PH20 
expression in neuronal cells, we cannot judge whether this model is relevant for 
investigating potential toxicities of anti-PH20 antibodies in enteric plexus or 
CNS.  Please respond to the questions communicated in our April 16, 2013 IR.  We 
remain committed to working together with you to promptly identify what if any 
additional studies should be done to support resubmission of the BLA.

Baxter Question 10.3.2
Will the Agency grant Baxter up to a 4 month extension (no later than 01 
November 2013) to respond to the CR letter? Within this time period Baxter will 
have reports from two GLP studies that assess male fertility and female 
fertility/EFD in rabbits.

FDA Response to Question 10.3.2 
The response to the CR should include a proposal for addressing any outstanding 
issues.  We commit to working with you to promptly determine what if any 
additional studies should be initiated.  When we review your reply to our IR 
questions, we will determine whether an extension to the CR response timeline is 
useful.

Baxter Question 10.3.2.a.
Can the Agency resume review of the BLA with draft reports of the two studies 
above with a commitment to provide the final reports within the first 3 months 
of the review cycle?

FDA Response to Question 10.3.2a. 
See response to 10.3.2, above.

Baxter Question  10.3.3
Does the Agency agree that the data described addresses the items in the CR 
Letter, and therefore a path to licensure can be defined?

FDA Response to Question 10.3.3 
We do not have sufficient information to determine whether the information you 
have provided is sufficient to address the possible toxicities of anti-PH20 
antibodies.

END
 

    
