Hello everyone, this is Dr Bishal Gyawali from Queen’s University, Kingston, Canada. Today I want to discuss about a certain trend in the FDA drug approvals, something that I refer to as ‘premature’ regular approval. Now, I want to discuss this in terms of breast cancer approvals.

Now, what I mean by ‘premature’ regular approval is that the FDA has two pathways for providing drug approvals: one is the accelerated approval pathway and the other is the regular approval pathway. The regular approval pathway is when there is certainty of clinical benefit, when there is no doubt about clinical benefit in terms of improved survival and quality of life, and the FDA provides full approval. Accelerated approval is on the basis of surrogate endpoints when there is still uncertainty in clinical benefit so they provide accelerated approval. Accelerated approval comes with a safety net filter that there is a mandate for the company to run a confirmatory trial and prove clinical benefit after which the accelerated approval can be converted to regular approval. If the company fails to do it, fails to do the trial or does the trial and the trial does not show clinical benefit, then the approval will be withdrawn.

However, what we have seen recently is that the FDA is offering regular approval on the basis of surrogate endpoints. One of the examples of accelerated approval that was withdrawn is bevacizumab in breast cancer. Bevacizumab got early accelerated approval because it improved progression free survival in metastatic breast cancer HER2 negative, but because it was accelerated approval they did a confirmatory study for overall survival and overall survival did not improve and bevacizumab’s approval was withdrawn.

But contrast that with everolimus. Everolimus improved PFS in hormone receptor positive breast cancer and the FDA gave up-front regular approval which I refer to as ‘premature’ regular approval. They did not wait for the OS when, in fact, previous experience was that in breast cancer PFS may not translate to OS and that’s why bevacizumab got revoked. Alpelisib in PI3 kinase positive metastatic breast cancer got up-front regular approval based on PFS. There are several other examples – margetuximab in HER2 positive breast cancer received up-front regular approval. In all these cases when overall survival results were published the overall survival was negative; the overall survival did not improve. But because they were not accelerated approval the FDA cannot revoke their approval – they are regular approvals, they are complete approvals – there is no safety net of withdrawing the approval.

In all these cases the time gap between getting PFS results and OS results is not substantial, it’s less than two years, it’s sometimes less than a year in most of these breast cancer examples. Less than a year in some cases, less than two years in almost all cases. So it’s not like we had to wait for overall survival forever. Again, I am not saying that these drugs should not have been approved at all; what I am saying is the FDA created a pathway called accelerated approval pathway for this reason, why are they not using it? If they are given accelerated approval instead of regular approval then the confirmatory trial results, these overall survival results, would have importance and the FDA can take action on the overall survival results. But because it was not accelerated approval and was complete full regular approval, the FDA cannot do anything even if the OS turns out to be negative.

I understand the difference between no approval and approval because patients want access to the drug so you can’t wait for overall survival forever, all these logics. But what is the logic for giving regular approval instead of accelerated approval based on surrogate? This is what I call ‘premature’ regular approval because even if the FDA gives accelerated approval the drug will be in the market, people who want to use it can use it and Medicare will pay for it. It’s not like the payment is stopped, there is a difference for accelerated versus regular approval. So what’s the motivation, what’s the logic, for the regulator to provide up-front ‘premature’ regular approval? All these drugs based on surrogates should have received accelerated approval first and regular approval once the survival results were announced.

Margetuximab, you will be surprised, it got approval based on PFS difference and that PFS difference is so minimal; the PFS difference is very, very minimal, I think it’s just a month or so PFS difference. Within less than a year they announced the results of overall survival which was negative, which was not significant. If margetuximab had received accelerated approval I’m pretty confident that it would have been pulled from the market. But because the FDA hastened the process and gave up-front ‘premature’ regular approval they can’t pull it off the market.

So this is a phenomenon I refer to as ‘premature’ regular approval and we all need to be cautious because the accelerated approval pathway exists for a reason and why is it not being used? This is a question that we need to ask because from physicians’ perspective, from patients’ perspective, there is absolutely no problem with accessing the drug if the drug receives accelerated approval. There is no need for us to say we need regular approval up-front. But by bypassing the accelerated approval pathway and providing regular approval up-front there will be no safety net trial.

Thank you.