- PGNX announced a 3-month extension to Azedra’s PDUFA action date.
- PGNX mentioned the extension was not related to safety/efficacy data.
- Some investors believe this means Azedra’s NDA has no safety/efficacy issues.
- There is no solid legal or regulatory basis for this belief.
THE PGNX PRESS RELEASE
On March 22nd, 2018, Progenics Pharmaceuticals, Inc. (PGNX) issued a press release where they stated that the Azedra PDUFA action date was pushed forward 3-months.
PGNX stated the reason for the extension of the action date: it was as a result of the submission of additional CMC (Chemistry, Manufacturing, and Controls) data on their part.
The extension is the result of the submission of additional Chemistry, Manufacturing, and Controls (CMC) information by Progenics, which required additional time for FDA review.
A POSITIVE VIBE
On the surface of things, this is very good news for investors, as CMC-related issues alone are some of the simplest to solve when compared to safety/efficacy concerns.
That being said, it would be remiss to forego the fact that only ~11% of CRLs are issued solely due to CMC related affairs. So if Azedra’s NDA does have CRL-worthy obstacles, it’s highly likely they’re not limited to CMC.
Yet PGNX went on to take the time to specifically highlight that the extension was not as a result of safety and efficacy related concerns.
The standard three-month extension is not related to the efficacy or safety data of AZEDRA.
This little insert, and more so the public misinterpretation of its wording by some, implied to many investors the “fact” that the Azedra NDA does not face any safety or efficacy concerns.
This misconception could not be further from the truth.
The legal and regulatory reasons for this are discussed below.
WHY THE THREE MONTH EXTENSION?
The FDA issued the standard 3-month extension because it considered the newly submitted information as significant enough to require additional time for review.
While not common, such delays are not unheard of by any means. Furthermore, investors should know that such extensions, on their own, do not mean that the drug will be rejected.
Plenty of drugs in exactly the same spot PGNX finds itself in now were ultimately approved even upon first review. So a small sigh of relief is in order.
A LEGAL LOOK AT THE PRESS RELEASE
But let’s underline something above: it’s the submission of such information that triggered the extension, not the request for information itself.
This means the FDA had requested the CMC information quite a bit ago but most investors only learned of the FDA’s request after PGNX responded to it, the extension was triggered, and the company chose to inform us.
This helps underscore the fact that the majority of the events behind a sponsor’s NDA review are completely confidential.
Ergo, a drug sponsor is under no regulatory/legal pressure to release much (if any) information on these events; nor any conclusions thereof (e.g. the reasons for a CRL, if issued).
By extension, PGNX has no duty to disclose any FDA-related inquiries in the interim either.
Now, some companies might voluntarily release a bit of information with respect to the NDA review in press releases, meetings, presentations, and the like. But if they choose to release any information, it doesn’t have to include the details investors want.
There are actually only a handful of “clear” legal rules with respect to a drug sponsor’s release of information as it pertains to all of the stages of drug development and approval.
Keeping in mind the fact that a few notable exceptions to the generally accepted rules discussed below have occurred, here are some of those rules:
1. Broadly speaking, a company isn’t obligated to release important information regarding any stage of drug development. The exception is that if some new information contradicts previously optimistic public statements on a similar matter, then PGNX must make the new info public.
2. More specifically to our case, if a statement about a stage of development/approval is volunteered, then that statement itself should not be false or misleading.
Consequently, because PGNX stated that the three month extension is not as a result of safety and efficacy issues, we should believe them and avoid assuming that it’s a false or misleading statement (otherwise it’s a serious legal matter).
Of course, the definition of what is “misleading” is controversial but that discussion is beyond this article’s scope and we presume it’s not relevant herein.
THE CRITICAL POINT
What’s more critical is that PGNX’s wording in the press release does not preclude the possibility that other requests for additional information were made by the FDA during NDA review.
Requests that may not have triggered a major amendment extension but were either:
1. Nonetheless qualitatively important.
2. Like the CMC matter, led to a large amendment early enough in the review process to help avoid triggering an extension.
These requests may have been on the safety and/or efficacy fronts; but we may never know either way unless PGNX specifically says none of this ever happened during the review.
THE REGULATORY MAZE
Now, all of that was more of a legalese look at the matter at hand. It’s important to turn our attention to the regulatory/FDA-related angle as well.
With that, we’ll be optimistic and presume two things:
1. Up until this point, PGNX never received a request for additional information on any safety/efficacy related issue during NDA review.
2. PGNX has been fully forthcoming on all of this to the public even if it had no obligation to be.
Does this ultimately preclude a CRL based on safety or efficacy issues?
Absolutely not; and we can boil down why not to the following points.
FURTHER REQUESTS ARE POSSIBLE
- When a request for information for one part of the NDA (like CMC) is made, this does not mean a request for information in another part of the NDA (like safety) will not be made at a later time.
The FDA is allowed to request additional information on a rolling basis. It doesn’t have to lump everything into one request. In fact, the former strategy is encouraged.
The FDA now has 3 additional months to review the new CMC info. Moreover, the 3-month extension does not limit the FDA solely to reviewing the CMC data. It can continue to review any other parts of the NDA it may need additional time for.
The FDA may also need to place the new CMC submission into context with respect to the non-CMC information; and this might change its ultimate conclusions about Azedra.
Keep in mind: only one 3-month extension is allowed so we need to hope that no major issue is found during these three months on any front (including the new CMC review) or else the application will definitely be rejected.
Ultimately the good news for PGNX is that, because the FDA has granted the extension, the FDA believes the new CMC information has the potential to resolve the FDA’s CMC-related concerns.
If the FDA thought otherwise, it wouldn’t bother with an extension for the major amendment. It would just issue a CRL on or before the original action date despite the new information.
THE FDA CAN CHANGE ITS MIND
- Even if a sponsor is preliminarily informed that no deficiencies in a portion of the NDA have been found, that doesn’t mean this portion of the NDA won’t prove problematic later on.
One potential reason for this is that there can be several different levels of specific and comprehensive reviews of the same data, which can override the conclusions of previous reviews.
This can occur quite late in the overall NDA review cycle as well.
SILENCE DOES NOT MEAN ACCEPTANCE
- During the NDA review, a lack of notification by the FDA that a problem has been found in a particular area is not necessarily a good sign. It’s possible that upon completion of the review a CRL will be issued for that area despite the sponsor being “left in the dark”.
Now, which of the latter three points is most appropriate in the case of PGNX is hard to figure out.
This is all slightly complicated by the possibility that PGNX may have submitted NDA data on a rolling basis and the FDA had the option (but not the obligation) to review things as they came in.
One thing is certain though: because the extension was triggered, PGNX submitted the requested info relatively late in the game.
But that doesn’t help us pinpoint how early the request was actually made and thus how likely it is that other issues may have come up during the review (and when).
THE ULTIMATE CONCLUSIONS FOR INVESTORS
So we’ll conclude this long legal/regulatory discussion with the following:
Yes, Azedra’s PDUFA action date was extended by 3-months. Yes, it was because of a CMC issue. Yes, this extension was not because of a safety/efficacy matter.
No, that doesn’t mean that there are no known safety/efficacy concerns worthy of a CRL. No, it doesn’t mean that none will be found within the next 3-months even if there are truly none at the moment.
Last Updated: 5/13/2018 for elements of style.
Author: Artem Cheprasov
No one associated with this article has any financial stake in, or ties to, PGNX.