A couple of quick points on the BLA based on memory of my research a while back:
- “Accepting” the BLA is a term with meaning. Upon receipt, the FDA has 60 days to respond to the firm and let them know whether or not the BLA filing has been accepted. This means only that the FDA feels that the submission is materially complete and the FDA can conduct an effective review. The other option is that the FDA can request more information from the firm, in which case that 60-day clock starts over when the firm provides the requested information. Rolling review should help some here, as the FDA should have in theory already looked at at least 1/3 of the filing.
- Upon notifying the firm that the BLA is accepted, a new clock starts, and the FDA then has six months under the PDUFA to respond with approval, rejection, or a Complete Response Letter (CLR). This last one is basically a “no, but...” and allows the firm to correct issues and resubmit. The FDA could also ask for additional data in a CLR. If the FDA issues a CLR, the firm must correct the issues in the filing, resubmit, and the whole clock starts over. This is quite common with issues in the CNC portion of the filing, which is why it’s huge to have Samsung on board helping with that. A minor issues with correct drain placement in your production facility could cost you a year...
- The rolling review that the FDA granted should also help get this approved before the six-month date if all is in order. Also, a minor correction to a previous post - the firm has not been granted accelerated approval, which is actually a mechanism for speeding up/shortening the clinical process. The firm has been granted priority review, which is why the PDUFA date is six months from acceptance instead of (I believe) eight months. TNBC, on the other hand, will potentially be an accelerated approval candidate if the trial nails the surrogate endpoint of reducing CTC’s.
- The “approval upon acceptance” numbers being put out there sound correct, but incomplete. They’re actually “eventual approval upon initial acceptance”, and don’t reflect any potential delays to those approvals from the firm not having its ducks in a row for the BLA originally. So whenever we get impatient with the firm about the BLA, we should recall that it’s not uncommon to lose significant time due to minor, correctable issues with the BLA. For a small company especially, it’s incredibly important to get it right the first time.
- As I recall, a significant portion of the filings that are not eventually accepted are due to safety issues. We’re in the clear there, in my mind. With combo, I believe were undeniably clear of the efficacy bar as well. With mono that’s probably a hair more debatable, since HAART currently does a good job of suppressing viral load in most, but I think the combination of high (if not perfect) efficacy, lack of adverse effects, and lack of observed resistance where SOC treatment has issues with the last two should be plenty to clear the bar. It absolutely presents an advancement in treatment for many patients if the pivotal trial sustains or builds on the existing safety and efficacy data.
tl;dr - After filing the BLA, we should hear about acceptance within 60 days one way or the other, and hear about approval one way or the other within six months of acceptance. Issues with the filing would re-start the clocks. If accepted, we’ll almost certainly be approved eventually, but silly mistakes could delay it significantly. So whenever we get impatient about how long the BLA is taking, we should remind ourselves how long it’s going to take if the BLA isn’t perfect the first time.
- “Accepting” the BLA is a term with meaning. Upon receipt, the FDA has 60 days to respond to the firm and let them know whether or not the BLA filing has been accepted. This means only that the FDA feels that the submission is materially complete and the FDA can conduct an effective review. The other option is that the FDA can request more information from the firm, in which case that 60-day clock starts over when the firm provides the requested information. Rolling review should help some here, as the FDA should have in theory already looked at at least 1/3 of the filing.
- Upon notifying the firm that the BLA is accepted, a new clock starts, and the FDA then has six months under the PDUFA to respond with approval, rejection, or a Complete Response Letter (CLR). This last one is basically a “no, but...” and allows the firm to correct issues and resubmit. The FDA could also ask for additional data in a CLR. If the FDA issues a CLR, the firm must correct the issues in the filing, resubmit, and the whole clock starts over. This is quite common with issues in the CNC portion of the filing, which is why it’s huge to have Samsung on board helping with that. A minor issues with correct drain placement in your production facility could cost you a year...
- The rolling review that the FDA granted should also help get this approved before the six-month date if all is in order. Also, a minor correction to a previous post - the firm has not been granted accelerated approval, which is actually a mechanism for speeding up/shortening the clinical process. The firm has been granted priority review, which is why the PDUFA date is six months from acceptance instead of (I believe) eight months. TNBC, on the other hand, will potentially be an accelerated approval candidate if the trial nails the surrogate endpoint of reducing CTC’s.
- The “approval upon acceptance” numbers being put out there sound correct, but incomplete. They’re actually “eventual approval upon initial acceptance”, and don’t reflect any potential delays to those approvals from the firm not having its ducks in a row for the BLA originally. So whenever we get impatient with the firm about the BLA, we should recall that it’s not uncommon to lose significant time due to minor, correctable issues with the BLA. For a small company especially, it’s incredibly important to get it right the first time.
- As I recall, a significant portion of the filings that are not eventually accepted are due to safety issues. We’re in the clear there, in my mind. With combo, I believe were undeniably clear of the efficacy bar as well. With mono that’s probably a hair more debatable, since HAART currently does a good job of suppressing viral load in most, but I think the combination of high (if not perfect) efficacy, lack of adverse effects, and lack of observed resistance where SOC treatment has issues with the last two should be plenty to clear the bar. It absolutely presents an advancement in treatment for many patients if the pivotal trial sustains or builds on the existing safety and efficacy data.
tl;dr - After filing the BLA, we should hear about acceptance within 60 days one way or the other, and hear about approval one way or the other within six months of acceptance. Issues with the filing would re-start the clocks. If accepted, we’ll almost certainly be approved eventually, but silly mistakes could delay it significantly. So whenever we get impatient about how long the BLA is taking, we should remind ourselves how long it’s going to take if the BLA isn’t perfect the first time.
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