



Teleconference Memorandum - Provenge, March 1, 2007



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

Discussion:

Product topics:
  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.


Clinical topics:
  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.


 
 