FDA Criticizes Study On User Fees & Approvals
23 CommentsBy Ed Silverman // March 28th, 2008 // 1:18 pm
A study released this week found that the Prescription Drug and User Fee Act led to more recalls and an increased likelihood that a drug will receive a Black Box warning. The findings confirmed criticism that PDUFA is to blame for pushing the FDA to rush approvals and causing unanticipated safety problems.
The study in The New England Journal of Medicine examined outcomes for drugs approved two months prior to their PDUFA dates and those approved at other times and found that after PDUFA, approvals were grouped close to deadlines set by the law. “You see all this piling ahead of the deadlines, and you have the piling of error,” said co-author Dan Carpenter of Harvard University.
But the FDA disputes the findings and is sending a letter to the NEJM, according to The Wall Street Journal. And at an industry conference yesterday, an FDA official says the agency can’t replicate the findings, according to The In Vivo Report. The “FDA has tried to confirm the numbers that are in that article and we have been unable to,” Doug Throckmorton, deputy director at the FDA’s Center for Drug Evaluation and Research, told the crowd. “The numbers we have gotten are considerably different.”
He noted that the vast majority of new drugs are approved at or just before the PDUFA date and that differences between the FDA’s data and the study’s data aren’t small. “We have a group within the FDA that’s working to try to understand where that difference is because it’s considerable,” he said. You may recall, by the way, that the FDA’s new safety mandates and its inability to hire staff have caused the Office of New Drugs to give managers discretion to miss PDUFA deadlines (back story).
Peter Pitts
If I were a Carpenter or a Zucker or an Avorn, — the three amigos who penned “Drug-Review Deadlines and Safety Problems” (NEJM, 2008; 358: 1354-61) – I’d be greasing up the old spin machine.
Clark Nardinelli, director of the economics staff in FDA’s Office of Planning, told BioCentury that the agency has identified “at least two fundamental problems with the authors’ data. We don’t think their conclusions hold up.” The paper misclassified a number of reviews as standard that actually had shorter deadlines because they were priority reviews, according to Nardinelli. When the reviews are classified correctly, the association between approvals near PDUFA deadlines and increased safety problems disappears, he said. The paper also understated the number of black box warnings, Nardinelli said. FDA plans to submit its data and conclusions to the NEJM and publish them on its Web site, spokesperson Christopher DiFrancesco said.
And all this time we thought it was the pharmaceutical industry playing fast and loose with data sets.
Well, as they say in Harvard Yard, “veritas.”
Tom
The New England Journal took an enormous turn for the worse when it decided to become a big league player in the field of medical politics. Much like the once venerable New York Times, it abandons its customary reason and impartiality when it comes to all things involving pharma or the FDA, seizing upon and spinning any scrap of spurious evidence that advances its political agenda.
henry
Perhaps the FDA should review data provided by drug companies with such zeal.
Justice in Michigan
Lots of presumption going on. There may or may not be errors in the study, but Dan Carpenter has been a scrupulous researcher. In general, his findings have argued _against_ the “PDUFA-is-the-problem” narrative. So the suggestions of spining, political conspiracy, etc., may be speculations that say most about their proponents.
Let’s see how it shakes out.
Steve
Anyone notice that most of these studies are going out of Harvard? Wonder what’s that about…
Steve
That should be “coming”
Jean-Sidney Kindler
Wow Peter Pitts ex FDA man.
If you were an unethical fda man and I was a lady
Would I marry you anyway, and have your baby.
NO FLIPPIN’ CHANCE LOL.
Nathan
Here’s my perspective — from the research end of the business:
The FDA is under pressure from companies to complete the review of submitted NDAs. The reason is because the 20-year patent clock is ticking away while the FDA reviews data. That equals money going down the drain. The shorter the FDA review time, the more money the company makes. Why not “normalize” this by providing a minimum exclusivity lifetime for drugs approved by the FDA? That would allow the FDA to take their own sweet time evaluating drugs properly without significantly affecting potential future revenue that the drug will make.
I know, I know… this would have to happen worldwide in order for this to be effective. But it seems like something has to be done. It’s frustrating for me to see 10-15 years of a 20-year patent wasted away before a drug ever sees the market. It’s only going to get worse as drugs are further scrutinized and more extensive testing is demanded. That means drug costs are likely to be even higher as drug companies try to recoup their costs within ever shorter and shorter periods of time.
Justice in Michigan
I think this is an excellent idea. It has been seriously proposed by a number of people over the years - within and outside of industry - and it has been in the wind again.
As Nathan suggests, much of what goes wrong (when it goes wrong), has to do with the “make hay while sun shines” incentives. This could be good for everyone.
As I recall, the last time a version of this was proposed was as part of FDAAA, when “even” Bill Frist was in favor of banning DTC during the first two years a drug was on the market. Those two years would then be added to exclusivity.
I like Nathan’s concept better.
Justice in Michigan
There are actually several problems that could be solved by “creative thinking” on all sides, and one’s that have been major sticklers, including preemption. This probably requires a new thread. I hope we’ll have that chance.
Dr. Sal Giorgianni
As someone who worked on the original PDUFA legislation, I was then and now firmly convinced that this legislation is essential. The purpose of PDUFA is to make up for the funding shortcomings that Congress continually foists on FDA. Without the funds this piece of highly studied and debated legislation brings to FDA the health and safety of the American public would be at great risk. This landmark legislation passed because it addressed several very real, vexing and growing resource issues for the dedicated public servants working at this agency.
Many critics of PDUFA wrong mindedly and cynically try to magically peg every issue that comes up regarding drug approval on this act. A user-fee would not be necessary if Congress simply and properly provided FDA with all of the funds to do its job. We could all go home and not engage in any of these debates. But, that is just goanna happen, folks. In my wildest dreams, I cannot imagine what progress and talent FDA would have at its disposal if it did not have to deal with appropriations shortages. I do not think that the American public should count on Congress providing this agency with all the finances that it needs. Even now, with PDUFA the Congressional Purse strings-holders still cannot seem to find money for the agency to do its non PDUFA directed activities adequately, not the least of which is off-shore drug manufacturing inspections.
Every time allegations are thrown around that user-fees somehow or other sway FDA and lead to “big problems” after these are critically reviewed they have been proven baseless; time and time again. NEJM has been a long time critic of these user-fees, and that is fine. Such critical review is needed. I do hope the authors of this work cooperate with FDA to identify the non-reproducablity of the results.
Bob Freeman
Dr. Giorgianni, Your comments and perspective are appreciated. As to non-replication, I wondered out loud on another thread that the odds ratios aren’t that impressive and the CI spread suggests a lot of noise in the analysis. There could be, and this is a big “be”, that there are data quality issues especially related to the actual approval date. Regardless, the failure to replicate the original analysis is a problem.
I agree whole-heartedly on your assessment of the ongoing funding problems.
HorusCat
Nathan,
Your comments are right on the money, so to speak. I have wondered before why we just don’t start the patent clock ticking only when the drug actually hits the market. I did not think of the international aspect of it. I think I have said before that not only the increased safety scrutiny by the FDA, but also the need for more and more subset-targeted drugs will string out the development process to the point where actual drug life will be very short, thus keeping prices high.
Former pharma Marketing Exec
I think the crux of the problem is that the increase in knowledge about cancer and other diseases in general has allowed a number of drugs to be fast tracked through the system.
The cancer drugs do show major life prolonging benefits but in some cases serious SE’s are only realized after a few years on the market and depending on the patient size, data is harder to accrue.
Understanding the human genome has given us the ability to develop more precisely targeted drugs. The benefits of these drugs are so critical that they must be brought to market as quickly as possible. When you see patients who are near death, get up and walk out of the hospital after a few weeks on a pill, it is immoral to not provide that drug to every patient who could benefit from it.
This puts a serious strain on the entire system. The fast tracked drugs are under obligation to continue to provide ongoing data to the FDA.
Clearly, as pointed out, the FDA is challenged with it’s resources.
I do not think that user fees are entirely to blame in this case. Not to get too political, how good would it be if we diverted some of the “war” funds over to the FDA?
The FDA system needs to be brought up to date to be able to allow us all to reap the benefits of our new drug technology.
I am not sure patent issues matter in this sense. Since drugs will have a shorter life span, perhaps the patents could be shorter too. But not before the approval process at te FDA is fixed.
Justice in Michigan
Dr. Sal wrote:
“A user-fee would not be necessary if Congress simply and properly provided FDA with all of the funds to do its job. We could all go home and not engage in any of these debates. But, that is just goanna happen, folks.”
I agree - something I’ve been making noise about for a while here. And it is about funding. An earlier study by Dan Carpenter showed pretty conclusively that more money leads to faster reviews (surprise, surprise), regardless of where it comes from.
Before I read FME’s post, I was also going to make the same connection. Industry’s entire annual PFDUFA contribution is, yes, the equivalent of one day in Iraq. By federal standards, this is _not_ huge bucks.
Shifting issues slightly - anyone want to trade FDA preemption for an adequately funded, independent Office of Drug Safety? (Not totally disconnected from the OND; just not under their thumb.) We all know post-marketing is where the most serious problems arise, and only a small bit of PDUFDA money has finally been wrangled out to cover a tad of it.
Dr. Sal Giorgianni
A large number of FDA-Industry pundits have, to date, not been in favor of an office of drug safety review within the agency. There are many reasons I have not favored this, not the least of which is that it could never be independent if structured within FDA and every decision or opinion they would render would be subject to the same second-guessing as now goes on within FDA.
But, times and needs change. In thinking through the whole notion a bit more I now do favor this as a potential solution. With the continued issues that fly around drug approval, post-marketing surveillance and the need to maintain a reasonable time line for approvals of more and more sophisticated and potential problematic drugs and biologics something new needs to be tried.
My favorable view on this would be predicated on such an entity being fully funded, independent of FDA and with a chain of review and comment that insulates it from Congressional second guessing. OK, the latter may be a pipe-dream but two outta three aint bad. Maybe there is an area within CDC or NIH that could house such an agency. Possibly such a review office could be staffed by some of the dedicated folks within the Public Health Service as a way to insulate them a bit from Congress. Let’s all put on our thinking caps here. If something is not done to mitigate the current climate of criticism very few truly novel drugs or biologics will ever make it out of the pipeline and survive the current market. This is not an issue of helping the commercial interests of research companies but an issue of creating an environment that helps promotes the health of the public.
Former pharma Marketing Exec
JIM,
Independent Office of Drug Safety, Hmmm This needs to be fleshed out more, but it certainly sounds appealing….
Lisa Van S
Dr.Sal & Justice,
I spent a lot of time in DC trying to convince legislators to support the Grassley/Dodd Bill. We were quite close in the Senate. Good old Hillary wouldnt go for it. She supported the industry written version. But yet she tells the public,.. she’s not swayed by the Pharmaceutical Industry. Hmm reminds me of her Bosnia story. Maybe she should check out my nephews helmet, the one that was hit by an Iraqi Insurgents bullet.
Former Pharma,
Not Political enough for me!! My Nephew is heading back to Iraq for his second tour. Semper Fi !!!!!!
Justice in Michigan
The idea of such an independent office has been around at least since the 1970s, in a couple of reviews of FDA by the National Academy of Sciences. The usual model is the same division that we have between the FAA and the NTSB. There are those who responsible for getting the planes in the air. And those responsible for investigating what the heck happened when one comes down.
Not surprisingly, David Graham has supported it for years. Senior management in FDA has been against. The usual argument is that those who approved the drug “know most about it” and thus should not be excluded from deliberations of what happened if it fails. The response is that they would not be excluded. They just may not have final say. Graham et. al. argue that having made a decision to approve a product, and then having to withdraw it, creates an inevitable COI. On some level or other, one is saying (even if one couldn’t have known) that one’s initial decision was (in retrospect) the wrong one.
The major reviews of FDA have been split. The IOM ended up not supporting a fully independent board. As I recall, GAO went closer to doing so. And, as above, as did several earlier reviews from the NAS.
Everything depends on organization, funding, and power. If/when FDA preemption happens and only the FDA as we know it is enforcing accountability - and the inevitable disaster happens (which will make Vioxx look like a picnic) - I believe industry will wish very much they had supported such an initiative.
henry
of course industry funding the FDA creates bias. They are human and the pharmaceutical machine is not! Soreth alluded to that-Ketek transcripts where the FDA and the expert committee discuss the infamous fraudulent study ” that’s what they pay us the big bucks for” she said. however a politically dependent ‘independent body does not work either. -Ketek again, Eschenbach refusedto cooperate with Stupack and Dingle-obviously the influence of Bush, whose friends are very close to big pharma. What;s the answer? I don’t know, transparency, release of raw data to the public after all it’s the public who participate in these clinical trials and the data belongs to them in a sense.
Justice in Michigan
Lisa - Where is Grassley-Dodd now? Did it become part of the FDAAA with the independent ODS deleted (like much else)? Or is it still around? My sense was the former, but I hope I’m wrong.
Lisa Van S
Justice,
It is the Former,… as long as Hillary and Kennedy are on the HELP Committee,… rest assured IODS will never see the light of day. Industry has these folks in their back pocket.
Dr. Sal Giorgianni
Lisa Van S
Back after a bit of a university related diversion - darn, still have to pay the bills.
First a bit of a personal note: Our #3 son is deployed USMC - hooorah! Not in Middle East but deployed to Asia keeping an eye on things there. Hope yours stays safe
Now back to that independent agency idea. Yes, an independent agency for safety evals. (and or a presumably autonomous division within FDA) has indeed been around for a long time as Justice noted. But I do think that every idea has its time.
Very interesting perspective on Hillary, could be she may be in the mood to break ranks with Teddy these days. May be worth another try soon…dynamics there are going to change.
I am not sure what current PhARMA/BIO perspectives might be on this all but I do hope they change a bit (as they did regarding user fees) things as they are just do not add-up to anything helpful to their bottom-lines.