Why The FDA Issues More Refuse To File Letters
9 CommentsBy Ed Silverman // April 25th, 2011 // 8:01 am
Here is yet another possible indication that the FDA is getting still tougher with its approval process. A review of so-called refuse-to-file letters - in which the agency refuses to file an application for approval review - finds that these missives are no longer being received by only the small, most inexperienced biotechs. Rather, a growing number are going to big pharma.
Among big drugmakers receiving an RTF in the last two years were Pfizer, Novartis, Roche and Merck, as well as Gilead Sciences, one of the largest biotechs, according to Leerink Swann analyst Howard Liang. In fact, all but one was issued in the past eight months. And prior to that, none of the 17 RTFs sent since 1998 that he identified was issued to a top-tier biopharma, he writes in an investor note.
What might this mean? He speculates a little: “While it is not possible to firmly conclude that the pace of RTFs has increased statistically due to a relatively small sample size and lack of disclosure of all RTFs, the fact that even the most experienced companies receive RTFs suggests a change at the FDA.” This change may be due to the willingness of FDA commish Margaret Hamburg to get tough on enforcement.
But Liang adds that, more specifically, that the RTFs “may also be related to the recent FDA implementation of good review practices in an initiative called ’21st Century Review,’ under which reviewers are expected to frontload the review and identify ’showstoppers’ early. After a pilot program started in 2008, this process is being implemented to all Biologic License Applications and New Drug Approvals in fiscal year 2011.”
In identifying and reviewing 28 RTFs, he noted three common categories of “deficiencies” that might prompt the FDA to send such a missive: clinical data, which was associated with 11 of 28 cases, or 39 percent; chemistry, manufacturing and controls in eight of 28 instances, or 29 percent, and electronic files in seven of 28 instances, or 25 percent. These last two, he writes, are often correctable.
pic thx to ell brown on flickr
Dr. Ben A. Drill
The only thing playing here is politics at the FDA, which is sad.
industry insider
The FDA sets the bar so low on filing NDA’s, , even a snake would have trouble slithering under that limbo stick. Used to be the only legitimate excuse for an RTF might have been that someone forgot to send in a key CD with all of the 2-year carcinogenicity data, for example. That happened to me once, and got me on a plane to DC the next day, with the RTF reversed the following day.
With big time money bonuses for pharma managers beating deadlines, in all likelihood, the manager or director responsible for submitting the deficient NDAs probably get their five figure bonuses for meeting or beating the time line for submission. Such bonuses are usually not tied to factors out of the employee’s control, such as an RTF by the FDA. Thus one is incentivized to submit a garbage NDA without fear of consequences. Let the marketing guy worry about an approval date being missed later on after you’ve drop kicked the problem down the road a piece.
MsPiggy
Whether it’s sad or not is irrelevant…the reality is that this touted regulatory body is a political organization through & through…The FDA has out lived it’s usefulness…time for another more effective approach to drug & product safety regulation to be implemented in America…
cigaRHETT
That’s sad to hear these comments on the FDA, because I feel like the only two competent exports the U.S. has to offer the world are guns and drugs.
JQ
Industry Insider, spot on, you are true insider, knows exactly what’s going on.
a Different Insider
Insider is correct that industry executives are the main fault. I have worked with several clients on various types of submissions over the years and each RTF was driven by someones desire to meet deadline no matter what.
I find that the electronic submission process makes it much easier to identify missing or deficient data. The recent streamlining of the FDA review procedure has increased their ability to respond at this earlier phase.
I don’t believe that politics plays a role at the level of the individual reviewers. I have had many phone meetings with reviewers to discuss issues with submissions and have always found that they are knowledgable, concerned scientists.
industry insider
Different Insider is correct. There is no political gain for FDA in issuing an RTF, since most of the time, as you indicate, it’s usually something missing when they run their standard checklist. To me it would seem much worse for the company for the FDA to file the submission, only to reject it outright later on. Company’s don’t realize that they are being done a favor when they get an RTF for other types of deficiancies. In a way it’s like a freebie CRL, only better, since they are finding out much earlier what they have to do to make the submission better.
JP
In the short term, this is unquestionably a negative, since no Company would want to have its filing rejected.
On the other hand, if this is a ‘fixable’ problem, such as might be the case for an electronic filing, or for chemistry or manufacturing issues, learning about a potential problem sooner is probably a positive event. The sooner that you know, the sooner the company can take up corrective action.
Problems with clinical data are another matter. There are many ways in which these problems can arise, many of which might require a follow up trial. This is the quintessential ‘train wreck’, since another trial can mean tens ( or hundreds) of millions of dollars, and 3 to 4 years of delay in getting to market. Nevertheless, knowing earlier is better than knowing later, since it would give the company an opportunity to start a follow up trial sooner.
Linda D.
To me the article just indicates the FDA is putting forward a more well-defined pro-active process to notify companies earlier in the review process about potential problems that require corrective actions and generate a RTF letter.
This should be more beneficial as companies can make the appropriate changes earlier in their investment – hopefully they will monitor all RTF letters and learn from each other’s challenges and delays. This will give insight into FDA’s expectations and requirements by identifying the “key issues” that FDA is focused on.