


Information Request Email, June 12, 2012 - Hyqvia




  

 
From: Shields, Mark
Sent: Tuesday, June 12, 2012 1:35 PM
To: 'Blackshere, Angela L'
Cc: Reed, Jennifer; Scott, Dorothy
Subject: RE: Information request: Immunogenicity Issues STN 125402/0

Hello Angela,

A face-to-face meeting to discuss the results is not warranted prior to the 
action due date.

The Stage 1 studies you outline may provide useful information to support your 
proposed Stage 2 preclinical toxicology proposals. We have the following points:

In your evaluation of relevant preclinical models, please examine whether 
hyaluronidase expression occurs in enteric plexus in addition to male 
reproductive tissue.

In 6.1.1, please indicate which characteristics you intend to compare between 
cross-reactive and treatment-emergent antibodies. Examples may include subclass, 
determination of whether these two types of antibodies react with the same 
epitopes on rHuPH20 and tissues, affinity for rHuPH20, and other 
characteristics. Measures of antibody comparability and sources of antibody 
preparations for study should be defined and justified in advance of the study. 
Cross-reactive antibodies in IGIV given to pregnant women would be present in 
substantially lower levels than are treatment-emergent antibodies, limiting the 
value of current human safety data for IGIV in pregnant women. We note that 
autoantibody levels correlate with disease severity in some situations (such as 
anti-C1Q antibodies in lupus nephritis). Since cross-reactive and 
treatment-emergent antibodies may have qualitative differences as well, absence 
of fetal or developmental effects will not be probative of treatment-emergent 
antibody safety. Your proposal is that tissue binding by both types of 
antibodies, if these have comparable characteristics would obviate concerns. We 
do not agree, not least because of the magnitude of differences in levels of 
antibodies.

In 6.1.2, we agree that these studies may be useful, but they do not address the 
question of developmental toxicities.

In 6.1.3, we note that in mice, little if any transplacental transfer of IgG 
antibodies occurs, limiting the usefulness of this species for your proposed 
studies if you intend to assess the impact on fetal development.

Best Regards,

Mark A. Shields, RAC 
Regulatory Project Manager 
HFM-380  FDA/CBER 
Office of Blood Research and Review 
Division of Blood Applications 
301-827-6173 fax 301-827-2405 
email: mark.shields@fda.hhs.gov 
1401 Rockville Pike 
Rockville, MD 20852-1448

"THIS MESSAGE IS INTENDED ONLY FOR THE USE OF THE PARTY TO WHOM IT IS ADDRESSED 
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DISCLOSURE UNDER LAW. If you are not the addressee, or a person authorized to 
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From: Blackshere, Angela L [mailto:Angela_Blackshere@baxter.com] 
Sent: Tuesday, June 05, 2012 7:15 PM
To: Shields, Mark
Cc: Reed, Jennifer; Scott, Dorothy
Subject: RE: Information request: Immunogenicity Issues STN 125402/0

Thanks, Mark.  Has the meeting been scheduled?

Angela

*************************************

Angela Blackshere

Sr. Director, Global Regulatory Affairs

Baxter Healthcare Corporation, Baxter BioScience

One Baxter Way

Westlake Village, CA 91362

(805) 372-3050/Phone

(805) 372-3052/Fax

angela_blackshere@baxter.com

From: Shields, Mark [mailto:Mark.Shields@fda.hhs.gov] 
Sent: Friday, June 01, 2012 8:56 AM
To: Blackshere, Angela L
Cc: Reed, Jennifer; Scott, Dorothy
Subject: RE: Information request: Immunogenicity Issues STN 125402/0

Hi Angela,

Yes, we have your meeting request.

Thanks! 
Mark


From: Blackshere, Angela L [mailto:Angela_Blackshere@baxter.com] 
Sent: Thursday, May 31, 2012 8:05 PM
To: Shields, Mark
Subject: RE: Information request: Immunogenicity Issues STN 125402/0

Hi, Mark:

Hope you’re well.  Can you please confirm receipt by tomorrow of the proposal 
submitted by Baxter on May 29, 2012 as Amendment 021 to STN 125402, in response 
to FDA’s below May 3, 2012 correspondence?

Thank you and best regards

Angela

*************************************

Angela Blackshere
Sr. Director, Global Regulatory Affairs
Baxter Healthcare Corporation, Baxter BioScience
One Baxter Way
Westlake Village, CA 91362
(805) 372-3050/Phone
(805) 372-3052/Fax
angela_blackshere@baxter.com

From: Blackshere, Angela L 
Sent: Friday, May 18, 2012 3:50 PM
To: 'Shields, Mark'
Cc: Hunt, Douglas M
Subject: RE: Information request: Immunogenicity Issues STN 125402/0

Dear Mark:

Thank you for the response to Baxter’s clarification questions.  We are 
developing a proposal and should have it available for submission to FDA prior 
to the July 29 PDUFA action date.

Best regards,

Angela

*************************************

Angela Blackshere
Sr. Director, Global Regulatory Affairs
Baxter Healthcare Corporation, Baxter BioScience
One Baxter Way
Westlake Village, CA 91362
(805) 372-3050/Phone
(805) 372-3052/Fax
angela_blackshere@baxter.com

From: Shields, Mark [mailto:Mark.Shields@fda.hhs.gov] 
Sent: Thursday, May 03, 2012 6:47 AM
To: Blackshere, Angela L
Cc: Hunt, Douglas M
Subject: RE: Information request: Immunogenicity Issues STN 125402/0

Our Reference: BL125402/0

Baxter Healthcare Corporation

Attention: Angela Blackshere

Sent by email

Dear Ms. Blackshere:

We are responding to your email inquiry sent Tuesday, April 17, 2012 7:10 PM. 
(Attached below)

Please acknowledge receipt.

1)Does the email sent by Jen Reed below serve as the official IR letter from 
FDA?

Yes, the email serves as the official IR.

2)Is there a date that FDA is expecting Baxter to provide our proposal by to 
respond to Jen Reed’s point # II below?  [Point II:  Baxter should propose 
preclinical studies in relevant animal species and/or clinical studies to 
address these issues.]

Forwarding your proposal as soon as possible will be helpful. This will speed 
our progress in seeking expert advice (see item 4, below). 

3)   Does FDA have any further thoughts we should consider as we prepare our 
proposal?

The main goal is to propose preclinical studies that will provide additional 
information about whether high titer anti-hyaluronidase antibodies could 
interfere with fetal and pediatric neuronal or reproductive development over the 
longer term.  Impact on adults should also be considered.  The choice of animal 
should be justified on the basis of antibody tissue-cross reactivity in testes 
and enteric plexus.  We have internally discussed the value of a chronic 
lifetime study for toxicity assessment, designed with intermittent look-in 
periods, for example histopathological assessment at defined timepoints.  For 
fetal developmental studies, we note that guinea pigs are considered as a 
reasonable model of human transplacental transfer of antibodies, but primates 
have also been used.   However, we encourage Baxter to propose what you have 
determined to be optimal studies to achieve the stated goals.

4)   Has FDA had any further discussions/thoughts regarding an anticipated date 
for the BPAC meeting?
We are currently discussing a different (non-BPAC) route for seeking expert 
advice on what studies would best provide data to address our immunogenicity 
concerns.  CBER is planning to request three Special Government Employees (SGEs) 
who are experts, to assist in identifying appropriate studies and in evaluating 
your proposal.

5) Is FDA’s intention when approaching BPAC to request guidance on what data 
Baxter should provide to address your immunogenicity concerns or will FDA 
provide a position on the approvability of the file and ask for BPAC 
concurrence?  Can FDA provide an idea of the type of questions you are planning 
to propose to BPAC?

Our current intention is to obtain expert opinion on preclinical data needed 
from Baxter to sufficiently address immunogenicity concerns.  The need for BPAC 
at a later date would depend upon results of these studies.   If FDA has 
concerns about results of studies, we may ask the BPAC for their opinion on 
approvability of the file at some future date.

Best Regards,

Mark A. Shields, RAC
Regulatory Project Manager
HFM-380  FDA/CBER
Office of Blood Research and Review
Division of Blood Applications
301-827-6173 fax 301-827-2405
email: mark.shields@fda.hhs.gov
1401 Rockville Pike
Rockville, MD 20852-1448

"THIS MESSAGE IS INTENDED ONLY FOR THE USE OF THE PARTY TO WHOM IT IS ADDRESSED 
AND MAY CONTAIN INFORMATION THAT IS PRIVILEGED, CONFIDENTIAL, AND PROTECTED FROM 
DISCLOSURE UNDER LAW. If you are not the addressee, or a person authorized to 
deliver the document to the addressee, you are hereby notified that any review, 
disclosure, dissemination, copying, or other action based on the content of this 
communication is not authorized. If you have received this document in error, 
please immediately notify the sender immediately by e-mail or phone."


From: Blackshere, Angela L [mailto:Angela_Blackshere@baxter.com] 
Sent: Tuesday, April 17, 2012 7:10 PM
To: Shields, Mark
Cc: Hunt, Douglas M
Subject: FW: Information request: Immunogenicity Issues

Dear Mark:

This is a follow-up to the April 5 FDA teleconference and the April 11 FDA 
correspondence below:

1) Does the email sent by Jen Reed below serve as the official IR letter from 
FDA?

2) Is there a date that FDA is expecting Baxter to provide our proposal by to 
respond to Jen Reed’s point #II below?

3) Does FDA have any further thoughts we should consider as we prepare our 
proposal?

4) Has FDA had any further discussions/thoughts regarding an anticipated date 
for the BPAC meeting?

5) Is FDA’s intention when approaching BPAC to request guidance on what data 
Baxter should provide to address your immunogenicity concerns or will FDA 
provide a position on the approvability of the file and ask for BPAC 
concurrence?  Can FDA provide an idea of the type of questions you are planning 
to propose to BPAC?

Best regards,

Angela

*************************************

Angela Blackshere
Sr. Director, Global Regulatory Affairs
Baxter Healthcare Corporation, Baxter BioScience
One Baxter Way
Westlake Village, CA 91362
(805) 372-3050/Phone
(805) 372-3052/Fax
angela_blackshere@baxter.com

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