Nemesis18,
I explained this in another post in the not too distant past regarding a thread started by comments on GermanCol’s posts but since you asked I’ll point out the rational again.
First crossover design, asked for by FDA, was what was best for patients due to the invasive nature of the trial protocols which includes leukopheresis and the desire by patients to know that they would have access to the treatment created by their own cells and tumor tissue. Beyond this, the crossover insured that if treatment was actively working that a true SOC/placebo comparator would not be readily available due to this requirement. Remember that FDA was not working in a vacuum of evidence, they had Phase 1 data to look at before making their comments about how to set up the Phase 2 converted to Phase 3. When you add in the issue of SOC induced pseudoprogression where patients were crossed over to treatment prior to actually eventing they no longer could be a suitable comparator group because they never truly evented before receiving the treatment. Therefore, three groups eventually emerged from SOC/placebo. Those that never crossed over ( many supposedly very ill according to Dr. Linda Liau) those that crossed over due to SOC pseudoprogression without truly becoming a rGBM patient by actual event and the third group was those that truly PFS evented and crossed over to treatment. The problem has always been that treatment was expected to be active based on Phase 1 evidence and other so crossover created a likely active to active comparison more than active to true placebo.
Now you say why would regulators like FDA do this. Well, their guidance allowed for changes to be made by the company as long as they remained blinded if measures for treatment effect could be proven to be inadequate. The duration of the trial allowed the suspicion of pseudoprogression interference at the beginning of the change to the Phase 3 trial to become a well known and community wide accepted fact instead of just a suspicion. I believe both FDA, Dr. Linda Liau and NWBO knew this would happen and that led to the need for new treatment measures which are allowed under the exceptions to adequate and well controlled trials. In this case ECAs were independently developed and checked thoroughly for bias and endpoints were changed to OS so that both GBM treatment and rGBM treatment comparisons could be adequately if not perfectly made. The final “approval” of these measures does not come until FDA review although they also had to be “accepted” provisionally before a SAP would be utilized by a company for their analysis of data and submission of same to regulators under a formal review process for commercial manufacturing and sales of said product.
As far as regulatory examination, the regulators have had more than 15 years to look at all the data, properly guide and instruct and understand what NWBO, Dr. Linda Liau, Dr. Keyoumars Ashkan and others have signed off on and they will very likely use this example as a case study in future guidance resources because of the time taken to do everything as correctly as possible with the limitations that were always in play. Best wishes.
