Here is what is clear regarding the hold. After the regulatory hold on new screening of patients was put in place, several critically important activities occurred:
1) data was submitted to a regulator (assumed to be FDA) and ongoing conversations occurred
2) patients already enrolled in the trial continued treatment
3) patients in screening were allowed to enroll in the trial - LP indicated that she planned to complete the trial through OS
4) Early Access Program(s) which require regulatory approval and treated in most ways as a single arm clinical trial without enrollment limits were initiated and implemented.
5) Approximately 30ish patient entered the trial after halt and over 100 received active treatment under EAP.
6) construction of new manufacturing capacity in England continued
7) manufacturing partnership in Europe were renewed
8) additional sites were activated in the trial because the process to onboard a site for commercial purposes is similar to the research activation process (thus speeding the time to commercializations in those centers)
8) the company announced that it agreed to stop enrollment at 331 instead of the previously defined 348 and the hold from FDA was lifted in February.
9) the company announced that the primary event trigger of 248 was reached by February 2017 and indicated that it would take several months to reach the OS trigger and a few months after wards to complete data lock.
10) the company announced in June that they were approximately 1 month away from reaching OS trigger of 231 and that ONLY 7 SAEs have been reported.
That's the facts, Jack! Based on points 1-5 and 10 it can be concluded that the hold was not due to safety or manufacturing concerns as has been widely speculated here by naysayers.
For those not familiar with clinical operations within industry, it should be understood that initial data analysis typically precedes final data lock. Final data lock is a process of verifying clinical reports against source data and quality checking data entry at sites. Preliminary results can vary somewhat but generally the first read is very close to the final set. Thus, I believe the result at least for PFS and likely OS is and has been in hand. I also believe that if it were negative it must be immediately shared publically. Clearly raising funds with knowledge of negative results would be criminal.
My base theory has always been that the hold in August 2015 was initiated due to a futility review and DSM recommendation after viewing blinded data, but that extreme efficacy on PFS was presumed. EAP approval supports this theory as does several other clues along the way.
