August 15, 2007
From: Nancy B. Miller, M.D.
Subject: Clinical Comment regarding proposed analysis plan for adverse events
reported following administration of vaccines formulated with GSK’s
proprietary adjuvant systems containing MPL
To: BLA STN# 125259/0.8
Through: Joseph Toerner, M.D., M.P.H., Team Leader
cc: Helen Sullivan
Martha Lee, Ph.D.
Gopa Raychaudhuri, Ph.D.
This amendment contains the sponsor’s responses to CBER’s request during a teleconference on July 18, 2007. The sponsor was asked to supply an analysis plan for a meta-analysis of adverse events related to inflammatory neurological disorders (SAEs, unsolicited AEs) and also adverse events of potentially autoimmune etiology that are non-neurological, from all IND and non-IND studies which involve the use of MPL in humans from both GSK and Corixa sources.
A statistical review was provided by Dr. Martha Lee of CBER. A clinical assessment of the following was requested by Dr. Lee regarding the issue noted below:
“Section 3: Evaluation of the potential cases of inflammatory neurological disorders and adverse events of potentially autoimmune etiology that are non-neurological
The diagnostic validity of the events reported is expected to be variable and will depend mostly on the complexity of the disease and diagnosis and the experience of the reporting investigators or treating physicians. To ensure comparability of the findings across the projects and studies, the sponsor will also include an evaluation of the diagnostic validity of the reported cases of inflammatory neurological disorders, in addition to the all-encompassing analyses.
The objective of this evaluation is to classify the individual reports into three groups:
1. those reports that contain insufficient information to ascertain or refute the diagnosis
2. those reports that contain sufficient information to refute the diagnosis
3. those reports that contain sufficient information to agree with the diagnosis
For the last group, different levels of diagnostic certainty will be proposed. The sponsor intends to use an independent expert to perform the above evaluation. For these assessments the expert will be blinded to treatment group assessment. This evaluation will not be used in the main analyses, but will be primarily used in the exploratory observed/expected analyses and may also be included in any additional analyses (see Section 4).”
Clinical Response: We do not have an objection to the proposed assessment. It is desirable that the sponsor will have the events reviewed by an independent expert. We would just want to confirm that they include all cases in their meta-analyses, regardless of categorization. We would also ask them to confirm that all potential cases are being reviewed by the independent expert, and not just those in the third category (i.e., 3. those reports that contain sufficient information to agree with the diagnosis).
Comment for Sponsor:
1. Regarding your proposed evaluation of the potential cases of inflammatory neurological disorders and adverse events of potentially autoimmune etiology that are non-neurological as presented in Section 3, we have the following comments:
a. Please confirm that all potential cases are being included in the meta-analyses, regardless of categorization.
b. Please confirm that all potential cases will be reviewed by the by the independent expert, regardless of categorization.