FDA: No More Dear John Letters For Rejected Drugs
9 CommentsBy Ed Silverman // July 9th, 2008 // 9:38 am
The agency is revising the way it communicates to drugmakers when a marketing application cannot be approved as submitted, according to an FDA statement.
Under new regs governing the drug approval process, the FDA will no longer issue “approvable” or “not approvable” letters when a drug application is not approved. Instead, a “complete response” letter will be issued at the end of the review period to let drugmakers know an application is not yet ready for approval. The letter will describe specific deficiences and, when possible, outline recommended actions needed to win approval.
“These new regulations will help the FDA adopt a more consistent and neutral way of conveying information to a company when we cannot approve a drug application in its present form,” Janet Woodcock, who heads the agency’s Center for Drug Evaluation and Research.
What is not readily clear from this move is the extent to which it will be more difficult for anyone beyond the drugmaker to discern just how much more distance must be traveled before a drug can be approved. The current distinctions - approval, approvable and not approvable - offer some indication simply by their nomenclature. Here is the rule.
Currently, when assessing new drug applications, the FDA can respond to a sponsor in one of three types of letters: an “approval” letter, meaning the drug has met standards for safety and efficacy and can be marketed; an “approvable” letter, which generally indicates a drug can probably be approved at a later date provided a drugmaker offers certain additional info or makes specified changes (such as to labeling); or a “not approvable” letter, which means the application has deficiencies generally requiring the submission of substantial additional data before the application can be approved.
“Complete response” letters are already used to respond to companies that submit biologic license applications. The process for drugs and biologics will be consistent under the new regulations.
The agency says the revision, which goes into effect August 11, should not affect the overall time it takes the FDA to review new or generic drug applications or biologic license applications.
Justice in MI
I’m trying to figure out the implications here. I follow Ed’s summary. But are “approvable” etc. letters in the public domain now? That is, are they accessible on the CDER site or similar?
Will the “complete response” letter be public and accessible?
Ed Silverman
Hi Justice,
The letters themselves are not available, unless of course, a drugmaker wants to share, which is…never.
But at the moment, you can get some idea of where things stand if only because the FDA stamps its reply approvable, for example. That signals the drugmaker has hope, but only if it certain steps are taken. Those details may not be made public either, so the situation can remain vague. But that’s enough info to distinguish from the non-approvable, which means the FDA won’t be giving a green light.
Will a complete response letter be made public? I wouldn’t bet on it. Besides rivals, investors will want to know as much as they can, of course, about where a drug stands and so Wall Street’s interest in this should be keen (unless I’m missing something, which I sometimes do, you know). Perhaps someone may try to argue such a letter is material because a great deal is riding on a particular drug being developed and, therefore, the company should disclose some of the contents.
This cuts both ways. As an example,the FDA final rule notes on page 92 ( go to the link I’ve provided ) “In the past, some drug manufacturers expressed concern that a not approvable letter sent an unintended message that a marketing application would never be approved, which could adversely affect a company’s ability to raise capital.”
In any event, it will be interesting to see how this plays out.
Cheers
ed
Justice in MI
Much thanks, Ed. Yes, I was guessing it was factors as you suggest, but why guess?!
In general, I’ve been “impressed” by how much eventually shows up on the CDER site, although often in redacted form. I’m thinking of a particular instance I followed of label negotiations which went through about twenty permutations before the final label was agreed to. It was interesting to follow the back and forth (it one is interested in that sort of thing!). Not a detail left unturned.
As raised in another thread (I may have missed an answer) also still wondering in general how much FDAAA will contain, in practice, a company’s appealing an FDA label decision, ober what period of time, etc. If I were less lazy, I’d read the law.
But perhaps someone knows “off the top.”
CMC guy
JIM I had much the same reaction so posed the following questions on “Eye on FDA” blog (http://www.eyeonfda.com/eye_on_fda/) since there have been a number of informative past posts on “approvable” letters:
Is this just a matter of sliding from a position of “Yes once you do XYZ” to “No, until you do XYZ”? Is there more significance here?
Seems if move to “Thumps up/Thumps down” then could reduce other options. This does not address issue of potential “Conditional Approval” mechanism practiced elsewhere (EU) which may have value in certain circumstances to widen availability of promising treatments.
In terms of communications from FDA is typically always at the option of the companies and rarely completely disclosed issued beyond summary highlights. In addition to selective release of the entire contents due to potential of investor (over)reaction and not showing everything to competitors IMO there is also not wanted to be seen as publically reviewing/criticizing the FDA because fear of consequences (just like Umpires Calls in Baseball)
Henry
Under the Food Drug and Cosmetics Act (FD&CA)there approvable letters were never allowed. the closest that was allowed was a nonapproval due to minor disagreements over labeling with a 2 month response time to negotiate the final labeling.
Most approvable letters appear to be have simply been issued illegally, and this is specified in the FD&CA as being the responsibility of the Secretary of HHS.
The question people should be asking is why the sudden change in policy?
Before, a nonapproval letter clearly meant major safety or efficacy problems. Now it could mean anything from major issues as before or something as simple as failing to complete negotiations overlabeling or some minor ommission of data that was realized by FDA at the last minute.
Last week Fred Hassan went ballistic in the WSJ about FDA and was talking about withdrawing drug applications. Could there be a connection?
Justice in MI
Thanks to CMC and Henry. Henry, I’m not sure I follow all you said. Is the idea that, by shielding all such letters, there are no “signals” that could be misinterpreted?
Henry
I’m not sure what you mean by shielding.
The old way although illegal was ostensibly less open to misinterpretation however in practice FDA was givin approvable letters for drugs that really should have been given a flat out nonapproval, e.g. requestingadditional efficacy or safety data really should have resulted in a nonapprovable letter.
Now virtually everything will get nonapprovable letters, so you won’t be able to even guess the really nasty actors from the minor reasons for nonapproval. Plus it will give Pharma more ammunition to complain about FDA and how they’re keeping new drugs off the market.
Also each of those illegal approvable letters in the past was a violation of the FD&CA, per the penalty section of the FD&CA each of those letters being a violation of the FD&CA was a misdemeanor. Not only is the Secretary of HHS named as the responsible manager, but whoever else was signing those letters has opened themselves up to criminal prosecution and disbarment.
Henry
P.S.
I’m not sure about this but FDA also has a number of guidances and policies about when and how to write the equivalent of approvable letters especially for chemistry / manufacturing / control issues. These may also be illegal under the FD&CA. If they are then who’s ever in charge of overseeing FDA policies may or may not have actually violated the FD&CA his/herself but I sure would want to be be in their position and have to explain to Congress how you can approve policies that are in direct opposition to the FD&CA.
Henry
One last comment. The effective date is August 11th which with the same day as the beginning of Congress’s Summer Hiatus. If FDA management wanted to prevent Congress from looking into criminal activities associated with a drug review this is one way that they could do it for so long as an NDA is under review they can deny giving information to Congress as it might effect the diliberative process. So the question is there an NDA whose PDUFA due date is past where the reviews are completed and FDA is just sitting on the application and not issuing a nonapproval letter. If so then this could be Obstruction of Justice. Congress should ask FDA for a list of all PDUFA Due Dates for presently submitted NDAs and then look for NDAs and in particular NMEs for which the review cycle is past the PDUFA due date.