PSP Follow up with Sponsor Email, February 27, 2014 - RAGWITEK
From: Greenfeder, Scott [mailto:scott.greenfeder@merck.com]
Sent: Thursday, February 27, 2014 9:46 PM
To: Valenti, Elizabeth; Rivers, Katie
Subject: RAGWITEK Pediatric Plan milestone dates

Dear Betsy,
 The Merck team has met and below are our proposed milestone dates for the pediatric program for RAGWITEK. The in-field efficacy and safety study is the timeline driver for this development. Please note that these are our best current timeline estimates prior to conducting a full feasibility assessment. Due to the overall size of the program we will need to evaluate clinical sites in countries other than the US and Canada in order to meet the subject enrollment criteria. In addition, our prior experience in enrolling pediatric subjects into the GRASTEK program suggests that we will need to conduct the efficacy and safety study over several ragweed seasons in order to enroll the requisite number of subjects.

Safety and Efficacy in-field study

Protocol submission
 Q4 2014
 Study Start
Q2 2015
 Final study report/sBLA submission
 Q3 2019

Supplemental Safety study
 Protocol submission
Q2 2016
 Study Start
Q4 2016
 Final study report
Q3 2018
 sBLA submission
Q3 2019

Regards,
 Scott
Scott Greenfeder, Ph.D.
Director and Liaison
 Global Regulatory Affairs
 T: +1 732-594-1021
 Fax: +1 732-594-1030
scott.greenfeder@merck.com
 Merck Research Labs
 126 East Lincoln Ave.
 MS RY33-204
 Rahway, NJ 07065
www.merck.com
 Notice: This e-mail message, together with any attachments, contains
 information of Merck & Co., Inc. (One Merck Drive, Whitehouse Station,
 New Jersey, USA 08889), and/or its affiliates Direct contact information
 for affiliates is available at
http://www.merck.com/contact/contacts.html ) that may be confidential,
 proprietary copyrighted and/or legally privileged. It is intended solely
 for the use of the individual or entity named on this message. If you are
 not the intended recipient, and have received this message in error,
 please notify us immediately by reply e-mail and then delete it from
 your system.


From: Valenti, Elizabeth
Sent: Tuesday, February 25, 2014 2:56 PM
To: Greenfeder, Scott; Rivers, Katie
Cc: Valenti, Elizabeth
Subject: RE: Information Request for BLA125478/0

Dear Scott,
 Thank you very much for your quick response. When submitting the amended pediatric study plan through the Gateway, please also include a timeline for the following:

Final Protocol Submission Date
 Study Completion Date
 Final Report Date

Please submit this timeline as soon as possible. You may submit it via email prior to including it in your amended pediatric study plan that you will submit via the Gateway.
 Please let me know if you have any questions. Thank you, Betsy
Elizabeth J. Valenti, MPH, RAC (U.S.), REHS/RS
 LCDR, USPHS
 Regulatory Project Manager
 FDA/CBER/OVRR/DVRPA
 1401 Rockville Pike
 Mailstop HFM-481
 Rockville, MD 20852
 (301) 796-2640
elizabeth.valenti@fda.hhs.gov
 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: Greenfeder, Scott [mailto:scott.greenfeder@merck.com]
Sent: Tuesday, February 25, 2014 2:30 PM
To: Rivers, Katie
Cc: Valenti, Elizabeth
Subject: RE: Information Request for BLA125478/0
Importance: High

Dear Katie,
 Thank you for the below clarification and request for an amended pediatric study plan for BLA 125478 RAGWITEK received February 20, 2014.
 As per the feedback provided below, Merck will amend the pediatric study plan sent via email on February 14, 2014 to include the following studies:
1.One in-field efficacy/safety study powered to demonstrate that the point estimate of the change in Total Combined Score (TCS) is at most -15%, and that the upper limit of 95% confidence interval is at most -10%.
2.One 24-week safety study enrolling a sufficient additional number of subjects to detect severe or systemic reactions which occur at 0.2-0.3% among Ragwitek recipients in the overall pediatric development program.

As requested below, Merck will target the enrollment of 1000 subjects between the ages of 5 and 17 years exposed to RAGWITEK 12 Amb a-1 U between the two above studies. The studies will be conducted to stratify enrollment by age group (5 to 11 years of age and 12 to 17 years of age) and treatment arm so that approximately 50% of subjects fall within each age group in each treatment arm. Additionally, pre-specified and solicited safety monitoring will take place for all subjects. Merck will amend the pediatric study plan and submit the amended plan as an amendment to the BLA ASAP.
 Regards,
 Scott
Scott Greenfeder, Ph.D.
 Director and Liaison
 Global Regulatory Affairs
 T: +1 732-594-1021 
 Fax: +1 732-594-1030
scott.greenfeder@merck.com
 Merck Research Labs
 126 East Lincoln Ave.
 MS RY33-204
 Rahway, NJ 07065
www.merck.com


From: Rivers, Katie [mailto:Katie.Rivers@fda.hhs.gov]
Sent: Thursday, February 20, 2014 4:24 PM
To: Greenfeder, Scott
Cc: Valenti, Elizabeth
Subject: RE: Information Request for BLA125478/0

Dear Scott,
 We have reviewed your February 14, 2014, email, which included an amended proposal for clinical studies of Ragwitek in pediatric patients, received in response to the January 15, 2014, information request. Below are the questions posed in your submission, followed by CBER’s responses.
1.Does CBER concur that the proposed EEC study and in-field study will support licensure of RAGWITEKÔ in 5-17 year olds if they meet the above success criteria?

Please see response to question #2.
2.Does CBER concur that the total exposure to RAGWITEKÔ in the three proposed studies (~500 subjects exposed to 12 Amb a 1-U) fulfills the requested safety exposure from the January 15, 2014 communication?

We do not concur. As conveyed in our January 15, 2014, communication the safety database for the pediatric population should be adequate to detect severe or systemic reactions which occur at 0.2-0.3% among Ragwitek recipients. Therefore, we recommend that your efficacy and safety studies include at least 1000 Ragwitek subjects 5 to 17 years of age.

This proposed efficacy field study should be powered to demonstrate that the point estimate of the change in Total Combined Score (TCS) is at most -15%, and that the upper limit of 95% confidence interval is at most -10%. We understand that this will require enrollment of a larger number of individuals. However, if efficacy is demonstrated, then additional studies, such as an Environmental Exposure Chamber (EEC) study, may not be necessary in children aged 5 to17 years. The duration of exposure should reflect the duration of exposure that you will be requesting in the package insert. Pre-specified and solicited safety monitoring should take place for the full duration of the study for all subjects. In addition, please stratify enrollment by age group (5 to 11 years of age and 12 to 17 years of age) and treatment arm so that approximately 50% of subjects fall within each age group in each treatment arm.

We concur with the design of the proposed supplementary safety study in subjects 5 to17 years of age. However, pre-specified and solicited safety monitoring should take place for the full duration of the study for all subjects. This will allow comparison of the safety following administration of Ragwitek and placebo to subjects during the first 28 days, and comparison of the safety profile of placebo and Ragwitek in those subjects initially randomized to receive placebo. It will also add to the adverse event survey data during pollen season. In addition, please stratify enrollment by age group (5 to 11 years of age and 12 to 17 years of age) and treatment arm so that approximately 50% of subjects fall within each age group in each treatment arm.

We consider an EEC study to be supplemental and may not be necessary. However, because EEC studies are conducted in controlled environments and thus should produce better results than field studies, we expect that an EEC study will be powered to demonstrate that the point estimate of the change in Total Symptom Score (TSS) is at most -20%, and that the upper limit of 95% confidence interval is at most -15%.
3.Does CBER concur that the EEC chamber study would be sufficient to meet the PREA requirement for RAGWITEKÔ if the study does not meet the predefined standard for efficacy?

In accordance with PREA, for children 5 to17 years of age, you will be required to submit an assessment containing data that are adequate to assess the safety and effectiveness of Ragwitek and to support dosing and administration in this age group. To fulfill this requirement, we have determined that you will need a field efficacy study powered as described in Item #2. As noted above in Item #2, if you choose to conduct an EEC study, we will consider such a study as supportive or supplemental for effectiveness. However, we do not consider an EEC study alone to be sufficient to support approval in this age group.
 To avoid delay in the review process, please respond via e-mail by Tuesday, February 25, 2014, if not sooner.

Thank you,
 Katie
 Katie H. Rivers, M.S.
 Regulatory Project Manager, CMC1
 FDA/CBER/OVRR/DVRPA
 1401 Rockville Pike, HFM-481
 Rockville, MD 20852
 Phone 301-796-2640
 Fax 301-827-3532
 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 by e-mail or phone.
