The CROs report to the sponsor or the sponsor's designee: DMC. The CROs do not know when the trial ends as neither can accumulate enough events to when the study ends (248-primary endpoint events (progression or death); 233-secondary (death only)). The CROs provide monthly reports to the DMC chair. But, the DMC is only meeting every 4-6 months until the trial ends. So the efficacy reports that the DMC review are not always going to be scheduled. Bosch and Boyton are the Company representatives that are the trial protocol contacts. I suspect they get the monthly numbers on progression and deaths, minus any other details. And once an interim or endpoint is reached, they have the DMC perform its functions. The Company told us in that press release that they, the sponsor, will then have the DMC lock the data once the event numbers are reached.
Note the following from the 331-patients enrolled:
One CRO is managing the US patient population. The US was expected to enroll up to 216-patients.
One CRO is managing the expected enrollment outside the US: Germany's 87-Patients; UK's 24-patients; and, Canada's: 21-patients.
And from the protocol on the DMC's role:
15.6. DATA MONITORING COMMITTEE
The sponsor of the study, Northwest Biotherapeutics, is blinded to all patient efficacy data during the trial. Surveillance of emerging study data will be carried out by an
independent DMC. The DMC will include members with clinical and biostatistical expertise and will be charged with monitoring the quality and integrity of data and the adequacy of recruitment, compliance and follow-up. Members must disclose any conflicts of interest prior to review of any interim analyses. The DMC will monitor all AE and outcome events, and will identify safety issues of concern.
The DMC will meet before the study begins, at restart after the study pause which occurred in 2009 and 2010, and approximately every 4-6 months thereafter until the end of the trial.
Urgent concerns may require one or more unscheduled meetings in addition to the regularly scheduled meetings.
One member of the DMC will be designated as the Medical Contact for the study. The DMC Chair will receive monthly reports from the CRO or designee of all SAE and quarterly reports of all AE, identified by treatment received and including relevant information about each SAE or other AE. The independent Medical Contact shall consult with the DMC chair or other DMC member(s) regarding accumulating AE and/or request the DMC chair to call an emergency meeting of the DMC. Based on its findings at either regularly scheduled or emergency meetings, the DMC may recommend continuing, stopping, or altering the trial.
At its regular meetings, the DMC will review data on recruitment and on both safety and efficacy endpoints. The DMC will see data separated by treatment group.
Possible reasons for a recommendation by the DMC to stop the trial are an unacceptable excess of AE among patients treated with DCVax-L, an excess of primary endpoint events in the treatment group and insufficient enrollment into the study.
The DMC Charter will provide additional details regarding the responsibilities, reporting, and operational activities of the DMC.
15.6.1. Interim analyses
Due to the serious nature of the illness in these patients, and because the primary and secondary hypotheses are progression-free survival and all-cause survival, pre-specified stopping rules using well-established statistical methodology will be used to assess statistical significance. O’Brien-Fleming stopping boundaries with a Lan-DeMets alpha spending function will be the group sequential method applied to define the stopping
rules to correct for the multiple reviews of the data by the DMC. It is
expected that interim analyses will be done when approximately 60% and
80% of the follow-up is complete; however, the spending approach allows flexibility in the number and timing of interim analyses should it be
necessary. With this approach, interim tests early in the trial are
conservative and the reduction in the overall power of the trial caused by
interim testing is small. Specifics boundaries and the alpha spending
parameters will be detailed in a DMC document prepared and approved by
the DMC prior to the review of any data.
Note as planned, the DMC will review recruitment information (e.g., rates),
safety data, and efficacy results. The primary, and secondary, and tertiary
endpoints efficacy endpoints will be reviewed. They should be considered
within the context of a closed testing procedure, and in the order of the
stated efficacy hypotheses, specifically the primary endpoint
(progression-free survival) first, followed by the secondary endpoint
(all-cause mortality) followed by the tertiary endpoint.).
Efficacy will also be reviewed at the two interim analyses plus one final
analysis. Overall cohort (i.e., all data from the beginning of the study,
followed by the “vanguard” cohort – i.e. those patients originally enrolled
prior to the hold and followed up to the current time, and a “restart cohort”, i.e., those follow-up since the restart of the clinical trial (i.e., since August 2011). Although the primary view is towards all patients enrolled (i.e. overall cohort), a consistency of effect across subsets would be the primary intent of these additional cuts.
The DMC review will contain, but not be limited to, the following efficacy and safety analyses: patient enrollment/disposition, patient demographics/ baseline characteristics, AEs and of SAEs (both tabular and listings as
appropriate), discontinuations from treatment and/or follow-up, survival
(overall and progression-free survival) –displayed in graphic (i.e., Kaplan-
Meier curves) and in tabular formats, causes specific mortality, and selected lab data.
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