PMC Phase 4 request Email, March 28, 2014 - RAGWITEK	

From: Rivers, Katie
Sent: Friday, March 28, 2014 8:56 AM
To: 'Greenfeder, Scott'
Cc: Lacayo, Juan; Valenti, Elizabeth; Daugherty, Jon; Chattopadhyay, Rana
Subject: RE: Amended PMC surveillance study response for CBER comment

Dear Scott,

We concur with your revised proposal received via e-mail, March 26, 2014, for the postmarketing study of Ragwitek.
Please submit a protocol synopsis and associated time frame for protocol submission, study completion date, and final report submission as an amendment to your BLA, STN125478/0.

Thank you,
Katie


From: Greenfeder, Scott [mailto:scott.greenfeder@merck.com ]
Sent: Wednesday, March 26, 2014 7:48 PM
To: Chattopadhyay, Rana; Rivers, Katie
Cc: Lacayo, Juan; Valenti, Elizabeth; Daugherty, Jon
Subject: Amended PMC surveillance study response for CBER comment

Dear Rana, Katie,
We appreciate the March 24 feedback from CBER. Our responses to the CBER comments are provided below. Based on the CBER comments, we have modified our proposed postmarketing study program. Does CBER concur with the Sponsor’s proposal to conduct two studies as outlined below? One study will utilize claims data to address the need to accumulate data on an adequate number of patients to assess the incidence and risk factors for events occurring during extended periods of treatment. The second study will use integrated health care system(s) to identify events associated with starter packs. These studies will be conducted in addition to enhanced pharmacovigilance efforts to directly collect information from healthcare providers regarding early events.
Merck will submit final protocol concepts for these two studies once we receive feedback from CBER on this modified proposal.
Merck’s responses to CBER IR received 24 March 2014 are in red below:
a.We recommend that you conduct your study using an integrated health plan with linked electronic health data that includes capture of initial therapy onset, rather than a “claims based” data source as proposed. While the design/feasibility of this study would be similar to the study as proposed, a data source with capture of early administrations could avoid or alleviate this limitation. 

Merck agrees that claims data will be limited by the inability to capture starter-pack exposure. Thus, there would be no way to systematically capture outcomes of interest that occur with early exposures (first 5 days) using only claims data. However, there are also limitations using integrated health systems with linked electronic health data. The sample size in these types of systems is significantly smaller than a claims database. Thus, it is not clear how long it would take to accrue 10,000 patients. Additionally, it is not clear at this time which types of integrated healthcare systems will utilize the therapy. There are anticipated regional differences in the uptake of the therapy based on allergen exposures which would mean that placement of a study in an integrated system would need to take expected allergen exposures into account. Also, some integrated healthcare systems may choose not to add the therapy to their formulary or list of approved therapies. Feasibility analyses will need to be conducted to select the most appropriate integrated healthcare system taking all factors into account.

Merck’s new proposal is to conduct one study using an integrated healthcare system with access to EMR data and a second study using a health insurance claims database with access to medical records. The integrated healthcare system will pick up the events that are associated with the early exposures based on use of the starter-packs as well as events that might occur during longer term therapy exposure. The strength of the claims database will be to offer a larger sample size to assess the incidence and risk factors for the longer term outcomes (i.e. those that occur after the starter-pack exposure). The claims database study will aim to collect a minimum of 10,000 patients, if market uptake is sufficient, and will continue for 3 years. The EMR study will also run for 3 years but at this time we cannot commit to a minimum number of patients in that study given the uncertainties described above. In addition to the proposed integrated EMR and claims database studies, data obtained through enhanced pharmacovigilance questionnaires sent to healthcare professionals will be collected to supplement information on health outcomes of interest reported with early dose exposure.
b.Please clarify the percentage of patients that you anticipate will be started on the starter pack, as opposed to starting with a prescription that would be captured with a claim. 

Merck anticipates that more than 90% of patients will be started by using a tablet from the starter pack. Merck will encourage all physicians to utilize the starter pack since this would minimize the chance that patients would leave the office to pick up a prescription and then take the first dose outside of office.
c.Some patients may be provided more than one 5-day starter pack, delaying their entry into the cohort until dose 11 or greater. Please clarify the percent of patients that you anticipate would be given multiple 5-day starter packs. Please collect this data from your company personnel in pre-specified regions and include in the protocol. 

Merck will instruct physicians to provide only one starter pack per patient. Based on prior experience with samples approximately 50% of patients may receive more than one starter pack. For this reason, Merck will also be conducting the study using the integrated health system to capture events associated with early exposure.

It is not possible to have our company sales personnel collect information regarding physician intentions for use of the starter pack before the approval of GRASTEK since this behavior would be considered pre-approval promotion of an unapproved product. However, Merck’s collective experience indicates that many physicians currently provide patients with 2 to 4 weeks of therapy via samples when starting new products, regardless of therapeutic category. Merck will also track the amount of starter packs left with physicians after approval, but will not have a method to collect how many starter packs are given to individual patients. Merck could conduct market research surveys to ask this question after approval.
d.Please provide more details regarding your planned time frame following product administration during which outcome measures will be identified (7 days, 14 days, 30 days).

The primary analysis will assess patients while exposed plus a 7 day grace period at the end of the estimated last exposure to capture any non-adherence. A sensitivity analysis may use a longer grace period (i.e. 14 days). A secondary analysis will limit the exposure period to the first 30 days.
e.Please clarify if you intend to capture all new users of product and outcomes of interest at any time during the year, regardless of the allergy season. 

Merck will capture all new users of product and outcomes of interest regardless of the time of the year.
f.We recommend that the study be continued for a full three years, regardless of the number of patients enrolled.

Merck agrees to conduct the studies for a full 3 years.

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 
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From: Rivers, Katie
Sent: Monday, March 24, 2014 1:42 PM
To: 'Greenfeder, Scott'
Cc: Valenti, Elizabeth
Subject: Information Request - BLA125478/0 - Postmarketing Commitment (PMC)

Dear Scott,

We have reviewed your March 14, 2014, e-mail submission of your Phase 4 PMC protocol concept for Ragwitek, BLA125478/0 and have the following comments:

Cohort identification is based on dispensing claims for all new users of Ragwitek. In the protocol synopsis for Ragwitek that was submitted via e-mail on March 14, 2014, the Limitations section indicated that “Initiation of therapy, however, will occur in physicians’ offices using sampled product, and patients will be given a 5 -day starter supply. Allergic events occurring before the initial prescription claim will be not be systematically detected using claims data.” We note that, due to lack of capture of allergic reactions at the onset of therapy, the interpretation of the calculated incidence rates will be limited to describing incidence in patients who tolerate initial therapy, not all exposed patients.
a.We recommend that you conduct your study using an integrated health plan with linked electronic health data that includes capture of initial therapy onset, rather than a “claims based” data source as proposed. While the design/feasibility of this study would be similar to the study as proposed, a data source with capture of early administrations could avoid or alleviate this limitation.
b.Please clarify the percentage of patients that you anticipate will be started on the starter pack, as opposed to starting with a prescription that would be captured with a claim.
c.Some patients may be provided more than one 5-day starter pack, delaying their entry into the cohort until dose 11 or greater. Please clarify the percent of patients that you anticipate would be given multiple 5-day starter packs. Please collect this data from your company personnel in pre-specified regions and include in the protocol.
d.Please provide more details regarding your planned time frame following product administration during which outcome measures will be identified (7 days, 14 days, 30 days).
e.Please clarify if you intend to capture all new users of product and outcomes of interest at any time during the year, regardless of the allergy season.
f.We recommend that the study be continued for a full three years, regardless of the number of patients enrolled.

Please submit your final PMC protocol concept as an amendment to your BLA or let us know if you require further clarification.

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.


From: Greenfeder, Scott [mailto:scott.greenfeder@merck.com]
Sent: Friday, March 14, 2014 9:18 AM
To: Valenti, Elizabeth
Cc: Rivers, Katie; Vaillancourt, Julienne
Subject: RE: Information Request for PMC, STN 125478/0

Dear Betsy,

Attached please find a cover letter and protocol concept for the PMC Phase 4 study requested below. In the interest of time, we are sending these today via email. We will submit to the BLA early next week.

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: Valenti, Elizabeth [mailto:Elizabeth.Valenti@fda.hhs.gov ]
Sent: Friday, February 28, 2014 3:18 PM
To: Greenfeder, Scott
Cc: Rivers, Katie; Vaillancourt, Julienne; Valenti, Elizabeth
Subject: Information Request for PMC, STN 125478/0

Dear Scott,

Please submit a protocol synopsis for a postmarketing commitment (PMC) to conduct a Phase 4 safety study of Ragwitek in the population for whom the product would be approved in the US. In your protocol synopsis, we advise you to conduct a study in approximately 10,000 subjects who will receive Ragwitek as indicated and to follow them for the occurrence of local and systemic adverse events (AEs) that result in medical attention (e.g., epinephrine use, hospitalization, and/or an ER visit). However, your proposal may include your own proposed sample size with a provided calculation and a justification that is supported with data. Also, in this study, potential risk factors for any AEs that occur should be assessed as secondary objectives based on information obtained in evaluation of events. Such risk factors would include, but not be limited to month of year when event occurs, age, antecedent interruption of therapy, and use of any concomitant medication including allergen immunotherapy.
Please submit your protocol synopsis as an amendment to your BLA.
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.

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.
