What Does “Approvable” Mean?

J0316822 There is a lot of word afoot that there are more approvable letters than there used to be.  An approvable letter is one of 3 outcomes from the FDA review process, other than approved and not approvable.  It can mean that the FDA wants more data, wants label revisions, wants some post-marketing studies, or has other questions.  But has the rate increased?  That is hard to document directly, but anecdotally, it does seem to be true.  Recently, In the Pipeline carried a posting on this issue – Disapproval of Approvability

Approvable letters are no fun.  It makes investors edgy, careers hang in the balance, people get very upset, the agency can be very mysterious and it overall creates an environment of uncertainty that benefits no one.  If in fact it is true that there are more fo these, and the world is becoming a more unhappy place, what does it mean?

It could mean that companies are not doing as good of work as they used to, but that seems doubtful.

It could mean that the agency is swamped with applications and is short staffed and so is issuing these to slow down the approval process.  Also something I doubt.

It could mean that the agency is feeling that they have to slow things down because they want to proceed with extra caution.  While not that exactly, I do suspect it is related. 

There are many drugs that are coming to consideration where the clinical trials were designed before the COX-2 fallout and are being considered after the COX-2 fallout. 

At the very long 3 days worth of advisory committee meetings held on the COX-2 safety issue, several AC members stated more than once that the "paradigm" on safety had shifted.  Clinical trials, it was said, would have to be larger.  They would have to be longer.  They would be more expensive.  But there were no specifics given, only general indications that what had been acceptable before was no longer the ideal. 

What, then, is a company with a drug that is under consideration under the "new paradigm" to do when its clinical trials were designed under the "old paradigm?"

For one thing, it means it is important that each drug sponsor who is operating under this circumstance not be making their case for approval under the old paradigm.  Rather, it is incumbent to fashion your case not as if you were being approved for clinical trial design and execution as it was when you began your Phase III trials, but by asking questions that are motivated by today’s mindset. 

Like crisis work, I often find when working with companies that are bringing a new drug to market, they fail to work hard enough to poke all the holes in their own arguments.  Rather, they spend so much time building their case, they come to believe it so wholeheartedly, that other perspectives become difficult to entertain.

If you have a product coming to market, you almost have to bring someone from outside inside to restore your perspective.  Someone who isn’t going to tell you what you want to hear, but rather what you need to know.  This is someone who will not view your clinical trial through the lens of a time machine, but should rigorously apply criticism and demand messaging around shortfalls. 

And, while that is good advice I lend for free, the truth is that the smoke is not yet cleared from the post-COX-2 fallout, putting product sponsors today in a rather untenable position.  Without specific guidances on exactly what the paradigm shift demands of them, coming to FDA with a new product will be a more inexact science than it was before. 

A bit more along these lines tomorrow…

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