From: Hithe, Darlene
Sent: Wednesday, April 15, 2009 10:24 AM
To: 'Pakulski, John'
Cc: Miller, Daryll L; Gemignani, Helen S
Subject: BLA 125296 Questions Regarding Post Marketing Surveillance
Your BLA is under review by CBER and we have the following comments in regard to post-marketing surveillance. Please submit your response as an amendment to the BLA by April 29, 2009, in order to avoid an extension of the review clock.
- You indicated in the Sentinel Surveillance Plan, the comparison group will consist of military recruits who never received the Adenovirus Type 4 and Type 7 vaccines but received concurrent mandatory vaccines, either in the prior year (historic control group) or within the same year (concurrent control group) but at different training sites.
- Please clarify what the concurrent mandatory vaccines are and when those vaccines will be administered.
- Please clarify whether the same set of mandatory vaccines were also given to the historic control group following the same vaccination schedule in the prior year.
- Please provide additional information on matching criteria and matching procedure for each control group.
- Please clarify what sample size will be used for each control group.
- Please clarify how long the cohorts (one exposed group and two unexposed groups) will be followed after vaccination. For example, how long will the 100,000th military recruit (the last subject of the Sentinel Surveillance Plan) be observed for potential adverse reactions after being exposed to the Adenovirus Type 4 and Type 7, Live, Oral vaccines?
- Please clarify whether censoring will be taken into account in the measure of incidence.
- The pregnancy registry study (p.16 of 51, section 4.1. /1.1) lists one of the inclusion criteria for women as “Female U.S. Military recruits in basic combat training, newly graduated from basic training and in active duty or discharged early from recruiting training”. Please provide additional information to define new graduates.
- The pregnancy registry study states that:
(p.26 of 51, section 5.4. /5.4.1) "Prospective reports are reports of pregnancy exposures to --(b)(4)--- provided to the Registry before the outcome of pregnancy or before a birth defect is noted on a prenatal test. Those pregnancies with normal outcomes identified on prenatal tests are considered prospective and included in the analysis. Those pregnancies with birth defects identified on a prenatal test will be included as retrospective cases and analyzed separately."
(p.27 of 51, section 5.4./5.4.2) "Retrospective reports: A report is considered retrospective when the pregnancy outcome has occurred at the time of reporting or a birth defect has been identified on a prenatal test. Such reports are accepted by the Registry but are analyzed separately from the primary analysis."
(p.33 of 51, section 8.1.) "Retrospective cases: This cohort includes all cases enrolled after the pregnancy outcome is known or suspected to be abnormal at the time of enrollment through prenatal testing."
It seems that retrospective cases include both prospective reports and retrospective reports. However, in analysis of retrospective cases (p.33 of 51, section 8.1.), only retrospective reports will be included. Please clarify.
- The pregnancy registry study (p.27 of 51) states duplicated reports will be considered “invalid”. It does not seem appropriate to mix those reports with other invalid reports in Summaries unless specifically labeled. Please clarify how duplicate reports will be specifically labeled to differentiate them from other invalid reports.
- Please provide an estimated time frame for recruiting 340 live births for the Pregnancy Registry study.
- In your discussion of viral shedding and risk for transmission (Section 4, DR-5001 Risk Evaluation and Mitigation Strategy) you note that "the greatest health risk associated with viral shedding and transmission is expected to occur when a recruit is discharged from the military within the 28 day shedding period following vaccination and comes in close contact with civilians at risk for severe ARD." You also note that this risk "appears to be low and can be further minimized by educating patients about the live nature of the adenovirus vaccine, viral shedding in the stool, the importance of personal hygiene, and avoiding close contact with vulnerable individuals in the civilian population if discharged early from basic training." Your proposed risk management plan includes targeted patient education, a prevaccination briefing, and a vaccine information statement leaflet to be made available to all vaccinees at the time of vaccination. (Section 4.3.2).
While educating vaccinees to these risks at the time of vaccination is important, it would seem equally important to provide an additional targeted education session as to these risks at the time of military discharge to those few individuals who are discharged from the military during the 28 day shedding period. A reminder session such as this at the time of discharge would seem to be an important additional strategy to minimize this risk. Please clarify whether a risk education session provided at the time of discharge to those who are discharged from the military during the 28 day shedding period is, in fact, a component of your risk management strategy for minimizing transmission. Please describe how this type of targeted educational session may be added if this type of risk management intervention is not included in the current plans.
Please consider this e-mail as a formal request for information. No fax or letter will be sent separately.
Regulatory Project Manager
1401 Rockville Pike, HFM-478
Rockville, MD 20852-1448
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