Eye on FDA

What is PDUFA?

 I used to have a much beloved co-worker who was not in healthcare, but upon hearing the term "PDUFA" - standing for the Prescription Drug User Fee Act - for the first time during a meeting, shouted out "What the hell is PDUFA?"  After that, PDUFA became his nickname.  Almost no one called him by his real name, everyone called him PDUFA.  

I regularly monitor the search terms people use when they use a search engine and land on Eye on FDA.  I like to see the most common uses and I also like to see the most uncommon uses.  Google Analytics shows you both.  Two of the most frequent search terms or phrases is as follows:

• PDUFA
• What is PDUFA?
• What is a PDUFA date?
• List of PDUFA dates

What is perhaps even more surprising is to see where some of these requests are coming from.  That is beyond our scope today, but I thought that the frequency of the search merited a special posting.  So if PDUFA is already well-known to you, you may want to stop here.  Or you may want to read on and kindly amend in the comments section any oversights I might have made.

What is PDUFA?  PDUFA, as noted above, stands for the Prescription Drug User Fee Act, originally passed in 1992.  In its most simple terms, the legislation authorized the FDA to begin collecting fees from drug sponsors that would be utilized to expand review staff so that new drugs could be reviewed more quickly.  The act has been periodically reviewed and expanded upon through reauthorizations and is currently in its fourth iteration.  

What is a PDUFA date?  The new system established set time periods for the FDA to review a new application, usually set at a 10-month period.  If a drug, however, gets a priority review designation, then the review time will be set at 6 months.  (A priority review is given to drugs that offer a significant new breakthrough in treatment, or offer a treatment where none or few exist, and can be given for a drug which treats a serious condition as well as those that treat less serious conditions).  The timing for the clock to tick begins when the company submits the new drug application to the FDA.  The date is a target for FDA, but the agency can, and many times does, announce a decision prior to the PDUFA date.  

List of PDUFA Dates.  While there are some companies that perform competitive intelligence and assemble PDUFA dates, and many investors will track PDUFA dates, there is no official "list" that is published by FDA.  That is because the filing of the new drug application and its contents are proprietary to the company that made the filing.  Many companies reveal the date of their filing by press release, while some do not - and there are various factors that go into that decision.  

It is also worth noting that a PDUFA date can be extended by the FDA.  This happens when the agency simply needs more time due to a circumstance in the consideration process - to peg down a risk management program or, more likely, to review new data.  

And, an alternative to this definition of a PDUFA date, of course, is going out to dinner and/or a movie with my friend PDUFA.  

Hopefully this brief and topline overview is helpful for the many, many people who each day enter search terms into search engines seeking some information on PDUFA.  And be careful asking out loud "What is PDUFA?"  It is a nickname that sticks.  

Hurry Up and Wait - Delaying Priority Reviews

Earlier this year the FDA Director of the Office of New Drugs John Jenkins indicated that the agency would have a decreased ability to meet PDUFA dates, saying that the agency was short-staffed.  Congress has also been investigating the use of accelerated approval and priority review.   Combined, these among other factors, have created a chilling effect on the approval of new drugs.  Dr. Jenkins noted that the manufacturer of any product that would experience a delayed approval date would be notified. 

On Friday, such a notification went out - to GlaxoSmithKline.  The company announced that their priority review application for Promacta^® (eltrombopag) for the short-term treatment of previously treated patients with chronic idiopathic thrombocytopenic purpura has had its PDUFA date extended by the FDA until September 19, 2008 - which now makes it kind of a non-priority review.   The Oncology Drugs Advisory Committee voted unanimously (16-0) on May 30 to recommend approval.   

This is perhaps a troubling signal for the year, but should also remind investors, analysts, companies and patients that PDUFA are not carved in stone and that advisory committee votes that are unanimous don't necessarily signal an effortless review process. 

Leaving PDUFA Alone

PDUFA IV, as has been noted here many times, is up for passage in the Congress.  For those new to it, PDUFA is the Prescription Drug Users Fee Act which, if authorized, will provide a majority of funding for FDA enforcement activities.  Many decry that situation, but also as noted here before, user fees are employed by many agencies across government and the European Medicines Agency (EMEA) also is heavily underwritten by such fees.

Recently,  House Committee on Energy and Commerce Chairman John Dingell (D-Mich.) and Frank Pallone (D-N.J.) sent an inquiry to FDA Commissioner Andrew C. von Eschenbach asking what the timeframe would be for FDA to have to begin workforce reductions without PDUFA funding.   The rationale, according to FDA News, is to better understand the time frame for the Congress to have to do its work.

There is a lot of FDA-related legislation that has been proposed in the 110th Congress, as those visiting the blog site can see off to the column at the right (those who subscribe by email or RSS feed will have to visit the site to see it).  It is sometimes been rumored that there may be attempts on the part of some to attach these pieces of legislation to the PDUFA legislation as an add-on.

Such a move is ill-advised.  Patients are reliant on the FDA to consider new medicines and get them approved quickly - that is why PDUFA was conceived in the first place.  The fact that PDUFA fees among some quarters are controversial and perceived as undercutting the agency's objectivity, makes it essential that this legislation be considered on its own, unencumbered by other contentious proposals.   PDUFA IV, which I support in spite of unanswered questions on its implementation from FDA, deserves consideration on its own and patients whose lives are hanging in the balance deserve nothing less. 

DDMAC Enforcement Down - PDUFA Dollars Up - What is Wrong with that Formula?

As we are in the midst of approval for PDUFA IV, there has been a lot of talk from the FDA about the need for increased funds to bring greater focus on drug safety and even monitoring of marketing activities.

But if you look at the track record over the span of all the PDUFAs, one sees a curious thing.  As PDUFA dollars go up, the enforcement actions by the Division of Drug Marketing Advertising and Communications (DDMAC) have gone down.

We have gone from a high in 1998 of 156 Warning Letters to the all time low set last year with 22.  For the first quarter of 2007, DDMAC issued a paltry 4 Warning Letters, which amounts to an annualized rate of 20 if that trend keeps up for 2007.

YEAR                # OF DDMAC WARNING LETTERS

2007                                                 4   (first quarter only)

2006                                               22

2005                                               29

2004                                               23

2003                                               25

2002                                               28

2001                                                64

2000                                               75

1999                                              108

1998                                              156

1997                                              139

This necessarily leads to a question I've asked before.  Are the large number of DDMAC Warning letters issued in the 1990s reflective of the fact that industry just wasn't very good at compliance and has now gotten much better?

This sort of track record should be explained because it is precisely the point raised by detractors of user fees - that the larger the portion of the enforcement budget comes from industry, the less aggressive is FDA about enforcement.  I support PDUFA IV, but there needs to be an explanation for this and it should be made clear before PDUFA IV is enacted. 

Warning Letter Volume on the Decline

The very day after posting about the upcoming FDA meeting on PDUFA IV, I was getting ready to check out the Warning Letters for the 4th Quarter when I decided to look back on the DDMAC issued letters going back to 1997.  It revealed something rather astonishing.  At this time, while FDA is asking for more PDUFA funds for enforcement, the number of Warning Letters issued by the FDA has drastically gone down over the course of the past 6 years.  In fact, the number of letters issued for 2006 hit a new low and was about 1/6th of the amount issued in 1998 when there were far fewer dollars raised from PDUFA fees for enforcement. 

2006 -22

2005 - 29

2004 - 23

2003 - 25

2002 - 28

2001 - 64

2000 - 75

1999 - 108

1998 - 156

1997 - 139

As an interior decorator I know would say, "less is more".   Perhaps back when DTC was new, there were more violations, but the irony still persists that the FDA is seeking more for DTC enforcement with this track record. 

While I don't swear by each of these numbers (they were hand counted and I'm not an election official from Florida), the bottom line is that the number of Warning Letters issued by DDMAC has clearly diminished over time, with some months of the 1990's producing nearly as many letters as some years during the 2000's. 

I'm interested in your comment.   

PDUFA IV Meeting Announcement

In today's Federal Register, there is a whopping entry published from FDA regarding that publishes proposed recommendations for PDUFA IV that will cover years 2008-2012.  Whopping refers to its length- 11 pages in PDF!  It makes good reading if you are interested in making the commitment, if not, I've summarized it for you below. 

The FDA is required to publish these proposed regulations and to hold a meeting to garner public input.  That meeting is now set for February 16, 2007 from 9 A.M. until 5 P.M. and will be held at the Grand Hyatt Washington at Washington Centre, 1000 H Street, Washington, D.C. 20001.  If you plan on attending, you much register by February 2, according to the notice, however they fail to state how one registers.  If you have questions, however, the contact listed is Ann.Sullivan@fda.hhs.gov  or her telephone number at 301-827-5887.

If you can't attend, you can supply written comment and the FDA is required to hold a 30 day comment period.    If you are using snail mail - you would send your comments to Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Room 1061, Rockville, Maryland 20852 or, if you are hip to the 21st Century, you can submit them electronically to the open FDA docket.

The notice outlines a very complete history of PDUFAs I, II and III and sets out an outline of PDUFA IV.   It then outlines the various meetings held with stakeholders over the course of time reflecting what was required of PDUFA IV, including meetings with consumer groups and professional groups.  As a result, they are publishing what they want from PDUFA IV, which fall into three categories:  (i) ensuring the sound financial footing of the human drug review program; (ii) enhancing pre-market review of applications, and (iii) modernizing and transforming post-marketing surveillance.  They also introduce another element - to review DTC television commercials.  There is a table in the notice to describe the commitment of resources to each activity, without the DTC component, which is noted in a later, separate section.

I am a believer in relatively short postings, therefore for  more detail and to see the tables, click on the above link. 

PDUFA Fees to Raise Money for Ad Reviews

And now, for a commercial break.

At the precipice of the Congressional turnover, the FDA has reached a tentative agreement regarding the review by the agency of television commercials.

According to the Wall Street Journal last week, pharmaceutical companies would pay a sum from $40,000 - $50,000 for each television commercial that they plan to air during the year.  The goal of the agency is to raise $6 million dollars in order to hire new staff to review those ads. 

If you ask me, it would seem like they could get that off the commercials run during the Evening News Hour alone.

Notably, for the Wall Street Journal piece (to which I would link you, but unlike most newspapers that are on-line, they require a subscription) neither the FDA nor the industry organizations would comment.  Thankfully, the Kaiser family foundation has a synopsis for you. 

But this PDUFA development does beg the question that has been raised here before.  As Congress demands more mandate upon the FDA, the costs associated with them go up.  Congressional critics cannot increase the mandates on the FDA over industry and still decry the amount of funding coming from the industry through PDUFA fees, unless it is going to cough up the money. 

According to the WSJ article, a synopsis of which you can find at the Kaisernetwork.org, PDUFA fees generated about $300 million this year for the FDA and under the new negotiations, this would boost by a whopping 30%. 

FDA reform, it would seem, has to be considered in its totality, along with the price tag, or individual mandates will keep upping the PDUFA portion of the FDA budget.  That's fine with me, but for those who have a problem with it, they better speak up about the big picture, rather than talk each reform on an individual basis. 

This agreement also makes one wonder whether heavier scrutiny of Direct to Consumer advertising will satisfy those critics in Congress who want to bring a moratorium on DTC, or at least reign it in.  And does the agency's acceptance of fees to monitor advertising affect its policy position on that question?  I don't know the answer, but the question is an interesting one. 

What Will the Next PDUFA Look Like?

There is an interesting conundrum developing.  PDUFA - the legislation that allows for the collection of fees from the pharmaceutical industry to be applied to the FDA budget - is up for debate and reauthorization in 2007.  The elections will be over, so there won't be so many distractions.  Of course, elections are the year after, so who knows?

But, according to reports, there is going to be a push to increase PDUFA fees to cover post-marketing surveillance.  Already PDUFA fees are comprising a huge portion of the FDA budget.  This is perhaps not what PDUFA architects originally envisioned and during discussions of reauthorization, Congressional critics are likely to make that known. 

So for critics, this is a source of discomfort - to have the agency overseeing compliance receiving funding from the industry it is regulating.  It would appear a conflict of interest to some, though actually that has only been conjecture and no one has offered any evidence that that is actually the case.  I wish they would put up or shut up on this front, but it is not likely, particularly for those with the bully pulpit of a Senate seat.

But that is the conundrum for the FDA.  Even without the other side producing evidence, after all, a charge unanswered is a charge admitted.  How does the agency demonstrate that, by collecting more funds from industry, it is better positioned to protect public health?  It is an interesting question and one which, if the agency is going to seek these funds, the agency had better well address as they ask for them. 

To pretend that the question doesn't exist, does not do the agency any good, just like it does it no good to pretend that the Plan B fiasco is not political, which they continue to do despite the fact that it is detrimental to their greater cause.  But to proceed to ask for funds without addressing the question of conflict of interest naturally opens the way for an opportunity for critics, even without a preponderance of evidence on their side, to prevail.  The agency does not appear particularly thoughtful in organizing their messaging, but they should get their ducks in a row on this one.

A Question on Risk/Benefit Budgeting

It is Friday and I tend to allow myself a little wiggle room on Fridays to wander far and wide, topically.

One of the reasons I'm really ready for Friday is that I attended the Pediatric Advisory Committee meeting this week on Wednesday that considered ADHD labeling.  The meeting had a theme - "Long Day's Journey into Night".  It began at 7:30 and lasted 11 hours.  If you didn't have ADHD when it began, you certainly did by time it ended. 

Dr. David Graham, with whom all are familiar, delivered an analysis that examined use of ADHD drugs within a closed system, which is his specialty.  However, during his analysis, he did something that actually made me laugh out loud.  He mentioned that the budgeting for his program for next year would be cut and therefore added something to the effect that he did not know how many of these types of studies would be able to be done in the future.

I'm  no purist, but the purpose of FDA Advisory meetings is supposed to be science.  This did not stop the chair of the committee, who appeared in no hurry to get home, from bringing this matter up before the committee as a topic of discussion, apparently unaware that they do not have Congressional budgetary authority. 

It did, however raise a question for me, and now I finally get to my point.  How much of the FDA budget is earmarked for risk analysis and how much for benefit analysis?  Is the public any more protected if the FDA focuses on exposing risk, or are they actually put at risk if the benefit side of the equation is also well enunciated?

I think some accountability is in order.  After all, the user fees are paying a good portion of the FDA budget.  Does it not seem that industry should know how their dollars are being used, just as Congress likes to know how its money is spent? 

I'm just raising the thought.  Have a good weekend.