Date\Time: March 1, 2007
CBER Representatives: Keith Wonnacott, Stephanie Simek, Celia Witten, Boguang Zhen, Peter Bross, Kimberly Benton, Mark Davidson, Tom Finn, Ashok Batra, Lori Tull
Sponsor’s Representative: Elizabeth Smith, Mark Frohlich, Lianng Yuh, Connie Spooner, Nicole Provost, David Urdal
STN : 125197/0
Subject: Product and Clinical Questions
- b(4) equivalency to 21 CFR 610.12
- CBER stated that Dendreon’s validation study may be acceptable, but in the head-to-head comparison, only b(4) microorganisms were used. Dendreon should provide justification for using only b(4) microorganisms. CBER suggested that Dendreon might see what data is available in the published literature to use as part of the justification. CBER stated that they would discuss with Dendreon at a later time the format for the submission.
- Dendreon responded that they had some historical data.
- CBER stated that the historical data may also be supportive. In addition to seeing data that supportive of equivalency it would be good if it also supported the b(4) incubation period.
- Rationale for not using the b(4) test
- CBER stated that Dendreon should submit justification as to why the b(4) test is not suitable for their product.
- Dendreon replied that the CFR states that the test is not required for products containing formed blood elements (FBE).
- CBER replied that Dendreon’s product is not an FBE. CBER stated that Dendreon did not have to do the test, but they did need to submit justification why they would not be doing it.
- Request more info on b(4) testing plan and retention sampling plan
- CBER asked Dendreon to describe their b(4). Dendreon responded that they were not planning to have one. CBER stated that Dendreon should submit their justification for this. Dendreon agreed.
- CBER asked for more details on the sampling of product for retention samples (i.e. timing, volume, handling, etc.)
- Request more info on logistics
- CBER stated that they needed to have a better description of the personnel in Seattle and New Jersey, their roles and responsibilities, and who makes decisions. CBER also asked for a description of which aspects of logistical planning were tracked in the computer system and which were not.
- Plans for product manufacture for continued study
- CBER asked for Dendreon’s plans regarding manufacturing clinical study lots. Dendreon responded that their long term plan is to b(4) that they have procedures for changeover, prevention of cross-contamination, etc.
- Status of 9902B in terms of enrollment rate.
- Dendreon stated that study 9902B had randomized 382 patients as of the end of February. They expect to enroll 12-14 patients per month; and expect to have 500 patients enrolled by the end of 2007.
- Demographics of the study and plans to expand enrollment of minorities.
- The study has about 4% African Americans. Dendreon is making efforts to enroll more African Americans, but have not had success so far.
- CBER asked if Dendreon had enrolled any Hispanics to the trial. Dendreon responded that they had about 2% Hispanics.
- CBER strongly suggested that Dendreon look for additional sites that have minority populations. CBER recommended contacting the major inner city hospitals, and also contacting the investigators for their thoughts on how to enhance recruitment.
- Dendreon agreed to renew their efforts to enroll minority subjects.
- Immunologic markers and upregulation measurements in the 9902B
- Dendreon stated that they think the upregulation of CD54 b(4)
- CBER asked if Dendreon had a sense of the normative ranges. Dendreon responded that b(4), the upregulation was less than b(4) fold. Once the cells were b(4) the upregulation b(4) was fold depending on the patient. Dendreon used a Cox model to evaluate the correlation and found a strong correlation with a small p-value.
- CBER asked how the immunologic health of the patient correlated to upregulation. CBER suggested that this could be addressed in the ongoing study. Dendreon responded that they did not collect data on immune competence in every patient. Dendreon stated that in study 9902B, they sampled from every patient and froze the samples in order to conduct assays in batch mode. CBER asked Dendreon to give a summary of what immune monitoring had been done and where to find it in the BLA.
- TTP adjustment clarifications
- CBER asked if Dendreon has submitted the narrative for the 10 patients that caused the changes in the p-values. Dendreon responded that they had, but understood that it was difficult to read. CBER asked if Dendreon could revise the appendix and provide a written summary in PDF for all 10 patients. Dendreon responded that the nature of the changes were a result of transcription errors and inappropriate censoring. Dendreon agreed to provide the information in a Word document.
- Leukopharesis clarifications (how many patients received more than 3 leukophereses)
- CBER asked Dendreon to provide information on patients who received more that three leukophereses. Dendreon responded that they are working on it.
- Pharmacovigilance - African American subjects, CVA's, risk of subsequent malignancies.
- CBER asked if Dendreon had a proposal for for following up the CVA events. Dendreon replied that they are developing a pharmacovigilance plan. They are planning for 3000 patients to receive questionnaires for CVA’s and malignancies. They plan to monitory for three years and then will use the national death index for patients alive after three years. For African Americans, Dendreon proposed that 300 patients may be a reasonable number.
- CBER stated that they were interested in reports of any plasma cell leukemias and any other malignancies. Dendreon responded that they planned to include secondary malignancies in their pharmacovigilance plan. CBER requested that Dendreon also look at their entire safety database for leukemias.