Hi Lykiri. I don't know where this European dimension came from to be honest. We know it was the FDA who lifted the hold, so one has to assume that it was the FDA who instituted the hold.
Though (whatever the issue was), it possibly emanated in Europe or Canada, though I doubt it. All jurisdictions just follow the lead of the regulator who took the action. And I would bet my bottom dollar that it was the FDA.
Having a provision to cross over to treatment, if the trial is halted early, due to perceived clear efficacy advantage to treatment at an interim, is not unusual. It would be built in to a trial's protocol, so the approval to do it would be granted up front. And being able to receive the investigational drug after a trial has been halted early is a bit like a 'reward' to control patients.
That's different to our crossover which is built in and is not determined by an efficacy finding. In our trial, the crossover provision would have kicked in, when the very first patient progressed. So why do sponsors offer a crossover after a trial is halted? Mainly as a recruitment incentive. And you only halt the trial early for efficacy, if as a sponsor, you are convinced that it will lead to some form of priority review and accelerated approval. If it doesn't lead to earlier approval, then the trial is effectively wasted, and so has been the patient commitment to being in the trial. These early halts for efficacy are usually based on a surrogate endpoint, so although you may get AA, you will likely get a load of post-approval confirmatory commitments. Halting the trial early, sometimes a few years only, obviously saves tons of trial expenses and shortens time to approval, thereby starting your revenue stream earlier (and often stealing a march on competitors). If Tocagen had got the early halt they were clearly hoping for, they would have likely secured approval in front of DCVax.
HTA's like NICE do not like these early halts for efficacy, because questions about extent of OS benefit almost always remain unanswered. And, a post-halt crossover has that confounding impact, making it difficult to calculate true OS benefit. So the FDA might give accelerated approval, but NICE might say 'the NHS will not pay for this treatment until we see a lot more OS data'. And rightly so, imo.
In my opinion (and I'm sure one or two may disagree), there is no way that the hold in our trial, and the unbalanced arm sizes was a result of an efficacy finding. For one, LL just wouldn't have made that statement about it being 'gratifying' to have the hold lifted, if the hold had been initiated as a result of a positive efficacy finding. But I'm not saying that the hold resulted from something 'bad' (like AV and his futility theory). I think it will have been for some fairly minor deficiency that does not have any bearing on treatment efficacy or safety. (CelSci had a partial hold imposed because the FDA didn't like something in their investigator brochure...)
Here is a NICE evidence summary on a breast cancer drug that involved a trial halt for efficacy, followed by a crossover, that may be of interest.
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