FDA Review Deadlines Caused Safety Issues: Study
12 CommentsBy Ed Silverman // February 1st, 2012 // 10:17 am
The latest buzz about the FDA is that the agency is approving more drugs in the past and, the trend has been especially noticeable in recent days with the approval of several medications, including a new type of treatment for some people who suffer from cystic fibrosis (see here and here). But what if the race to meet approval deadlines caused some unintended consequences?
A new study suggests that might have been the case. After examining data from FDA advisory committees, a group of researchers from Harvard University, Stanford University and Brown University found that a relationship exists between approvals made closest to deadlines and post-market safety problems, such as drug withdrawals, major labeling revisions or safety alerts issued by the agency.
Although the researchers do not maintain that a strict cause-and-effect relationship has been established, they suggest the implications ran wide and deep. To wit, in the quest to meet deadlines, approvals may have inadvertently led to adverse health outcomes - which raised costs for patients and payers - and caused setbacks for drugmakers that expect predictable financial returns.
The findings, which were published in the American Journal of Political Science, appear as the House Energy & Commerce Committee holds a hearing today on the virtues of the Prescription Drug User Fee Act (you can watch here and see the agenda here). Known as PDUFA, the initiative was first passed in 1992 and ushered in a new era in approvals as drugmakers now pay fees to fund reviews - these cover about 60 percent of the cost- and the agency has specific requirements to meet.
The purpose of the paper was to examine how Congress uses deadlines to control regulatory agencies, and PDUFA offered a useful lesson. “By imposing specific deadlines and linking agency compliance to the agency revenue source - the penalty for not meeting the deadline was not simply embarrassment and congressional pressure, but also the possibility that tens of millions of dollars in user fees would no longer be available for personnel costs - PDUFA represented a significant effort to influence FDA actions,” the researchers write.
To test their hypothesis, they examined the approval process for 1,034 new molecular entities that were approved between 1950 and 2008, when - the Food and Drug Administration Amendment Act - was passed and began to require advisory committee meetings for NMEs. What did they find? Well, the so-called review clock can be problematic. “Our analyses suggest that deadlines have altered the timing of FDA decisions,” they conclude.
For instance, they compared reviews before and after PDUFA began 20 years ago, and found that reviews suddenly piled up in as the six-month deadline neared for those drugs after the legislation went into effect. But there was no such piling in the years before PDUFA. This suggests that deadline pressure altered the timing of reviews and raising the possibility of post-market problems, since this may have compromised the ability of the FDA to gather and distribute info through advisory panels.
Moreover, they assert that, if a drug is approved in the two months before the deadline, then that same drug will, on average, experience higher rates of safety issues in the years after approval, compared both to drugs approved quickly, which was three or more months before the deadline, and to drugs approved more slowly, which would have been after the deadline.
Specifically, they found the probability of a drug approved in the two months before the deadline receiving a new black-box warning is 3.27 times greater than a drug approved at some other time, according to a model used to examine NMEs approved between 1993 and 2007. For NMEs approved between 1993 and 2007, safety-based withdrawal is 6.92 times greater for a drug approved in the two months leading up to its approval deadline than for comparable drugs approved at other times.
“The bottom line is that there remains a relationship between approvals at-the-deadline and the raised incidence of post-market safety problems several years later,” Daniel Carpenter, the Allie S. Freed professor of government at Harvard University and one of the researchers and the author of ‘Reputation and Power: Organizational Image and Pharmaceutical Regulation at the FDA,’ writes us.
“Although we are still not claiming baldly that the deadlines necessarily cause - in a physics-like notion of causality - these post-market problems, the observational evidence seems to be mounting, and the manuscript uses a variety of statistical controls and tests, including a form of statistical analysis called ‘non-parametric matching,’ to tease out the relationships,” he continues. “And it suggests that one mechanism for this relationship may be compromised consideration of the drug later in the review stage, including occluded or shortened advisory committee consideration.”
Observer
May I observe that my thoughts on this matter were similar and aligned with the Celebrex issues - and were actually rather common in the circles I have moved in over the years. Put it another way - “Speed kills..” as we used to say. Therefore may I also observe “This is news?”
NOTE - That comment is to the authors of the study and not to “our noble scribe!!”
ThatAgencyGuy
There is still much to fix with PDUFA; but missing in this argument and ‘analysis’ seems a key point.
During the Mid 80’s before PDUFA the average FDA approval timing was 29 months; while in even in recent years I believe its still under 17 months. Today thanks to PDUFA, 50% of all new drugs come first to the US, before PDUFA this was 8%.
So how many US citizens have benefited from getting their new medications a year earlier than before PDUFA?
John F.
Getting medications earlier doesn’t neccessarily mean that it is a benefit to the patient. It benefits drug company executives for sure. Adverse drug reactions are one of the leading causes of death and disability. I know this first hand as I now suffer disabilities from a pharmaceutical drug - Levaquin. It has been many years of suffering for me. Thousands of others have suffered long term as well.
Observer
@ThatAgencyGuy - May I observe that I have a great deal of respect for those who work at the agency - and for seeing good science come to fruition - but my earlier observation stands:
“Speed kills ..” - out of context but it applies
original industry insider
Here is the paper so that you don’t have to buy it. My conclusion is different. What actually happens at the agency is that the most diffeicult reviews, i.e. the ones with the potential safety issues are always last to be approved, giving the false impression that they are “rushed”. The “no brainer” reviews are dispached poste haste, further exacerbating the misimpression. The reality is that the clock on all NDA reviews starts within days after the dossier is received and accepted for filing.
http://onlinelibrary.wiley.com/doi/10.1111/j.1540-5907.2011.00544.x/full
ThatAgencyGuy
John - Certainly sorry for your condition; But adverse drug reactions are very far from a leading cause of death in the US. See Page 8 http://www.cdc.gov/nchs/data/nvsr/nvsr60/nvsr60_04.pdf
or disability
http://www.disabilitycanhappen.org/chances_disability/causes.asp
If pharma products caused this sort of damage we would have even more lawyers and even less pharma companies.
I am not saying the FDA or Pharma is perfect; however the vast amount of patients taking pharma products are healthier and living longer and better because of these products.
Also the regulatory system is a lot stricter and slower in the US; then anywhere else on the planet.
ThatAgencyGuy
@Observer Not THAT agency…
Dim Sum
Sanofi is currently in process of completing flu vaccine related project that the FDA is funding. Wonder what will come of success or failure to meet deadlines, ability to achieve goals, and why or why not.
It would be interesting to know in light of this article…
DS
STL
oii is exactly right. In my shop, the things that don’t go right up to the deadline are the no-brainers, which would be more than enough to explain the finding reported in this paper.
I’d be willing to entertain the possibility that decisions made on an accelerated review clock (i.e. priority review) tend to lead to less safe products. But that’s sort of built in to the priority review process - these are products with great potential for benefit (unmet need, etc.), and so more risk might be tolerable.
pharmacy reviews
Investigational New Drug Application (IND)–The pharmaceutical industry sometimes seeks advice from the FDA prior to submission of an IND. Sponsors–companies, research institutions, and other organizations that take responsibility for developing a drug–must show the FDA results of preclinical testing they’ve done in laboratory animals and what they propose to do for human testing. At this stage, the FDA decides whether it is reasonably safe for the company to move forward with testing the drug in humans.
dzieczko
@pharmacy reviews - thanks for going to the beginning of an IND - pre-clinical data.
Phase I - First in Man studies used to be evaluated based on a predictive model - the reviewers at one point were confident in shutting it down after Phase I based on what happened to one patient.
pharmacy feedback
PDUFA which links FDA funding to its ability to meet drug application review deadlines may be altering FDA review behavior. The study indicates that more reviews now pile up around the 6 month deadline than before PDUFA existed as legislation. Drugs reviewed and approved less than 2 months before the deadline is reached experience higher post-market safety issues than drugs approved more than 3 months before the deadline or after the deadline was reached. A new black box warning is 3.27 times more likely for a drug approved within the 2 month window, and safety related withdrawl is 6.92 times more likely for these drugs.