An observation off ASCO 2017 slides about Serious Adverse Events (SAEs)
First here is the information on SAEs slide:
"DCVax-L administered more than 2,000 times to the 331 patients in the Phase III trial
Only 7 patients had an SAE “related” or “possibly related” to the DCVax-L treatments or placebo - 5 nervous system disorders (e.g., seizure, edema); 1 gastrointestinal (nausea); 1 lymph node infection
*Generally, AEs were related to underlying GBM or SOC/other treatments: 132 patients had SAEs considered unrelated to DCVax-L
Rate of adverse events with SOC + DCVax-L approximately same as rate of adverse events with SOC alone. " -
And so, in total 132 patients had SAEs. They didn't say where these SAE occurred (before or after enrollment), and so it's unclear how many of them are related underlining GBM, to GBM standard of care or to "OTHER" treatments. And if only 7 DCVax-L patients had SAE. And the rate of AE for were approximately the same per cohort, to me, it indicates that SAEs mostly fall into the "other" bucket (I.e., Leukaphersis).
We also don't know if their manufacturer in the US, Cognate, first manufactured the DCVax-L vaccine supply (minimum of 5 injection) before attempting to make placebo 10-injection supply. I personally would not blame them if they made DCVax-L supply first. What is also unclear is how many patients needed to undergo the procedure more than once to meet the study design demand -- although the consent form covered consent for more than one leukaphersis if necessary. How often was it necessary?
Again, I speculate the "screening" halt was possibly related too many Leukaphersis SAE events, due to too many repeat leukaphersis procedures, which would have a cause for concern if it upon review of IRB renewals. To those who claim that Leukaphersis is unlikely to cause an SAE event, and would not cause a "screening halt", I point to this section of the SAE protocol, as it relates specifically to monitoring and reporting Leukaphersis events:
"13.3. RECORDING AND FOLLOW-UP OF ADVERSE AND SERIOUS ADVERSE EVENTS All AEs that occur (or that worsen from pre-leukapheresis status) from preleukapheresis through 30 days after the patient exits from participation in the trial or last study treatment, (whichever comes later), are immediately reportable to the Sponsor, or its designee, regardless of relationship to study treatment. A Serious Adverse Event Report Form must be completed and sent to that contact by facsimile within 24 hours of becoming aware of the event. Additionally, if there is any suspected relationship to the leukapheresis procedure or the study drug administration, the sponsor or sponsor’s designated contact listed in the study manual should be notified by telephone within the same 24 hours. A narrative from the investigator, outlining the details of the AE, its treatment, and its outcome is to be included on this form. Follow-up information, such as laboratory reports, discharge summaries, autopsy reports, and information concerning outcome of the event should be submitted only for SAEs deemed at least possibly related to study drug or study procedures such as blood draws, leukapheresis, or study drug injections, with a revised Serious Adverse Event Report Form as soon as the information becomes available. Northwest Biotherapeutics is required by regulatory agencies to report all serious and unexpected AE that are possibly, probably, or definitely related to the use of the study drug in clinical studies in an expedited manner. Therefore, investigators are required to provide timely completion and follow-up of the Serious Adverse Event Form.
In the event that a serious unexpected suspected adverse reaction (SUSAR) is reported, as required by local regulatory authorities, the Sponsor or designee may ascertain the treatment assignment and unblind the patient to assess the need forexpedited reporting to a regulatory authority. The treatment assignment will only be known by necessary Sponsor employees/consultants, or designees for the purpose of regulatory reporting. Procedures for unblinding are found in section 8.6 and will be described in the study manual and IXRS manual.
In addition to notifying the sponsor’s designated contact listed in the study manual of SAE, investigators are required by US regulations as described in 21 CFR §312.66 (Assurance of IRB Review) and EU safety reporting guidelines, to notify their Competent Authorities (CA) and Institutional Review Board (IRB)/Independent Ethics Committee (IEC) promptly of all changes in the research activity and all unanticipated problems involving risk to human subjects or others, and that the investigator will not make any changes in the research without CA/IRB/EC approval, except where necessary to eliminate apparent immediate hazards to humansubjects. This means that the investigator will report to the CA/IRB/EC all SAE occurring at the investigator’s study site(s). In addition, investigators are also required to report to their CA/IRB/EC all SAE that are immediately reportable to this study (i.e., Expedited Safety Reports/SUSARs), regardless of when the SAE occurred. In these situations, the sponsor or its designee will provide the necessary information to the investigator to report to their CA/IRB/EC in the form of an Expedited Safety Report Letter." - protocol
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