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Record of Telephone Conversation, August 14, 2009 - Flublok
Submission Type: Original Application Submission ID: 125285/0 Office: OVRR
Protein Sciences Corporation
Telecon Date/Time: 14-AUG-2009 11:08 AM Initiated by FDA? Yes
Author: TIMOTHY FRITZ
Statistical Reviewer (Barbara Krasnicka) Information Request regarding statistical items in PSC response to CBER CR letter of August 29, 2008.
FDA Participants: Timothy Fritz
Non-FDA Participants: Manon Cox
Trans-BLA Group: No
Related STNs: None
Related PMCs: None
Please address the following comments and questions related the submission of the results from pivotal study PSC04:
- There are some differences between the Final Study (FSR) and Interim Study (ISR) reports, despite the fact that relevant parts of these reports should be based on the same datasets.
You described the ISR analysis in the following way: “A formal interim analysis will be conducted after all enrolled subjects complete the Day 28 contact. All data collected at the time the last subject completes the Day 28 contact will be considered in the interim analysis. All immunogenicity, reactogenicity, and safety tables and listings will be generated as part of the Day 28 data analysis.”
In the ISR, you reported only 70 protocol deviations, while it appears that in the FSR as many as 100 protocol deviations were counted through Day 28 (Table 7, page 58). In the FSR, 577 (12%) subjects were counted as discontinued (Table 4, page 56, “PSC04 –Subject Disposition through Day 28 Contact”), while in the ISR only 188 subjects were counted as discontinued. Please explain these discrepancies.
Please also provide a diagram similar to your diagram on page 57, showing the subject disposition from Day 0 to Day 28 and from Day 28 to the end of the study, and an adequate SAS data set.
- The loss of 5 samples was not included in Table 7 (FSR, page 58) despite that these losses also should be considered as protocol deviations. Please comment.
- In the CR letter, Question #17, you were asked to check whether “Assay” has any influence on the statistical results (GMT) of lot-to-lot consistency. Based on your response (Response to Complete Response Letter, page 12), it appears that the statistical model that was formulated by you is not quite correct: “Treatment” should not be included in this model. Please redefine an appropriate model and additionally, please supply information on variability between lots and within lots by strain.
- For each pivotal study, please submit a SAS dataset that contains: Subject ID, Site, Treatment, Enrollment Date, actual length of time interval from Day 0 to ‘Day 28’ visit or discontinuation day and actual length of time interval duration from Day 0 visit to the last visit/call/discontinuation day.
Additionally, please demonstrate that for each pivotal study, the subjects’ actual duration of follow-up did not depend on the treatment group.
In your reply, we recommend that you restate our request and follow it with your explanation or clarification. Use of this format helps organize the relevant information and provides a self-contained document that facilitates future reference.