What They Said – Press Releases 1st Quarter 2017

Anyone who reads this blog knows that apparently I like to count things. Why? Well it provides the basis to confirm or refute general observations, and also can provide perspective that makes you stop and think and wonder. But if you didn’t stop and take note of what’s changed and what hasn’t, you might not stop and think at all. For some time now, I have followed FDA’s pronouncements to the public in the form of press releases and put them into a database. Here is the story they tell to date for 2017.

First of all, FDA is saying less. And less. Comparing the first quarter of 2017 with the same time period from 2016, the agency sent out 23 press releases during the first three months, compared to 32 last year. However, if you look at the first three months of 2015, FDA sent out 46 releases during the first quarter, twice the number for this year. So the trend is very much down.

When they did talk, what did they have to say? It would appear that when it comes to approvals, the agency is on par so far with last year at this time, but down quite a bit from 2015 which was a banner year for approvals. So the early returns – which are early – would indicate that 2017 is looking a lot more like 2016 than 2015 for approvals.

Looking only at one quarter gives us the beginning of some insight and perhaps serves to raise some questions for what we might look for in the coming year. For example, if the number of approval announcements stay at this rate next quarter, this year will look a lot more like last year. Looking at the rule-related announcements – last year there were 6 and this year 2 – makes one wonder whether the Administration’s 2 for 1 standard for issuing new regulations (add one, subtract two) – about which we’ve heard very little of late – has had an impact. And is the drop in legal actions (consent decrees, etc) reflective of a slow down in enforcement or is it just a blip? And finally, is FDA just getting more quiet over the years?  We’ll have to tune in next July to see how we are doing on these questions, and perhaps more to come.

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DTC and OPDP

It is a different era of enforcement. So far the first quarter of 2017 has not yielded a single regulatory action letter from the Office of Prescription Drug Promotion (OPDP). That said, in December of 2016 OPDP put out more letters in the month of December than had been issued for the preceding eleven months combined. So low enforcement does not mean no enforcement. It may come in lurches.

Next week I am speaking at the DTC Perspectives Conference in Boston providing some thoughts on how research being undertaken by FDA might impact DTC advertising. It seemed like a starting point for having that discussion would be to provide some context with respect to enforcement vis a vis DTC.

You could argue that all promotional speech is DTC.  In my database of warning and untitled letters put out by OPDP over the past several years, you can see a lot of different communications vehicles. This includes the obvious things like websites, broadcast ads, journal ads and then the not so obvious items like a puzzle, a belly band, or even a bathroom stall cling. They are all carrying a communication about a prescription drug product and all have been included as the subject matter of letters from the Office of Prescription Drug Promotion.

But for these purposes, I am looking solely at those promotional communications via traditional paid vehicles in various media – specifically, consumer print and professional journal ads, broadcast radio and television, and web-based banner advertisements.

Let’s first look at how violations in DTC compare to the violations that occur overall. This represents a look-back at all of the letters in the database going back through 2004 to present and compares the top violation categories – Risk Information (either omitted or insufficient), Superiority Claim, Unsubstantiated Claim, Broadening of Indication, Promotion of an Unapproved Use or Promotion of an Unapproved Drug. What you see is that in DTC there is a much larger proportional representation for the omission or minimization of risk information (represented in blue) and for making a superiority claim (represented in orange).

When looking solely to DTC itself, where have the violations occurred?

Interestingly the majority have been in print (combined 56 percent for print ads and journal ads) while only about a combined one-fourth have been in broadcast television or radio. Meanwhile digital has been only about one-fifth as well, despite the fact that by FDA’s own research in assessing 2253 submissions, the trends show that digital promotional pieces are on the rise while non-Internet promotions have been on an even plateau. Since the database goes back through 2004 and social media and internet ascendancy occurred during the latter part of that, one could argue that only later years should be examined. But if you look at enforcement from 2010-2016 vis a vis DTC, the contrast is even more stark. In fact, there appear to be no letters issued involving print ads, journal ads and broadcast television ads.

From this one would have to come to one of three conclusions. (1) Internet/Social Media DTC is done more compliantly than any other form of DTC; (2) After the great issuance of letters involving banner ads in 2009, there is no DTC in Internet/social media; or (3) FDA’s enforcement is not focused in the same place its research points.

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The White House on FDA Approval Burden – Is There a There There?

In his remarks to a joint session of Congress delivered this week, President Trump expressed the point of view that the “slow and burdensome approval process at the Food and Drug Administration keeps too many advances… from reaching people in need.” He went on to say that if “we slash the restraints” then we can ostensibly speed the arrival of new medicines.

But is it accurate to characterize the FDA’s process as slow and burdensome?  Are new treatments in fact being kept from reaching people in need?  Are people with rare diseases having their hopes for treatment quashed by an overbearing bureaucracy?

These questions are actually not new. In fact, they have been around for quite some time and most certainly came to a head when in the early years the HIV/AIDS epidemic was exacting a heavy toll and there were no treatments. How to speed approvals has long been a question that has always interested policy makers. And while the objective of doing so is everyone’s goal, experience has demonstrated that achieving the goal is more likely the result of a process than an event.

According to testimony submitted by the General Accounting Office before the Senate Committee on Labor and Human Resources in 1996 on FDA Review and Approval Times, in 1987 it took an average of 33 months for New Drug Applications (NDAs) submitted to the agency to be approved. This was during the early and very savage years of the AIDS epidemic when thousands upon thousands of people were dying without any meaninful treatment for their HIV infection. According to the same testimony, by 1992 – just 5 years later – the number of months to approve a new drug had dropped to 19 months.

More improvement was forthcoming. With the advent of the Prescription Drug User Fee Act (PDUFA) in 1992, the agency acquired new revenue that allowed for an expanded capacity to review NDAs with the consequence that approval times were reduced even further. To make a long story short, today PDUFA brought the consideration time for a new drug just 10 months in most cases, and even faster in special cases.

That is because in the beginning in 1992, new review mechanisms began to be introduced that would speed the consideration of important new drugs that would make a difference to people who had serious medical conditions. These new mechanisms provide enhanced pathways for new product consideration and include Accelerated Approval, Fast Track, Priority Review and Breakthrough Designation. Each contributes in its own way to moving an investigational molecule down the approval pathway by either speeding up the process or bringing in additional FDA resources. In addition, to encourage the development of drugs for rare diseases such as mentioned in the speech this week, there is Orphan Drug Status which qualifies a drug sponsor with incentives, including tax credits for qualified clinical testing,among others.

But do these mechanisms get used to help bring drugs to patients more quickly?

By my count in 2016 there were 32 FDA announcements involving drug approvals (I keep a database of FDA press releases).

  • A majority (18) of these were announcements of the approvals of drugs that were either not life-threatening/serious conditions or
  • where there were already other treatments approved (12),
  • approval of a biosimilar (3),
  • approval of a generic (1)
  • or approval of an OTC switch (1)
  • giving ok to an expanded label (1).
  • 14 were announcing approvals of treatments for serious and/or rare conditions or offered new ways to treat. Of those 14 announcements, all of them had either one, multiple or in some cases all of the enchanced pathways described above and 9 were orphan drugs. The approvals were in different areas of oncology, hepatic diseases and central nervous system disorders.

In other words, FDA is approving miracle drugs for rare conditions in which people were waiting for treatment and doing so in increasingly short periods of time. Great strides have been made since the days of the 1980s, and the progress has continued. FDA deserves credit, as do patient advocates.

It may be obvious to most that what the Administration is talking about is not the actual time FDA takes to approve a compound, but the burden of proof that drug sponsors must meet in order to gain approval. Or perhaps it is not so obvious. In any case, that is quite a different subject from a process being characterized as “slow” and perhaps one with quite a different outcome.

If the “slow” process referred to is one that requires speeding up drug marketing by lowering the burden associated with the development of data to show efficacy and safety, then it is really talking about the quality of new medicines. That again is a topic that the first generation of HIV advocates know something about – having mounted a movement to do just that.  We would do well to listen. As former AIDS activists and a former FDA Commissioner pointed out in an opinion piece in the New York Times last June, significant progress can be – and has been made in working with FDA to effect faster approvals.  That has been achieve not by working against FDA but rather with FDA. There has been significant progress in speeding up approvals while ensuring quality for both safety and efficacy in the medicines that are needed but faster approval should not come at the expense of quality and safety. That much should be clear to any new FDA Commissioner.

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AdComm Activity for 2016 – How Did They Vote?

The number of new drugs approved by FDA last year fell – by many indicators. There were fewer new molecular entities approved and there were fewer press releases about approvals during the year compared to 2015. And consequently, there were fewer advisory committees held to consider new drug approvals, but only just.

It is always interesting to look and see what kinds of decisions Advisory Committees made this year regarding product approvals and how does it stack up to what we’ve seen in the past. Looking back through my database going back through 2009, what observations can we make?  Here are a few.

  • Number of Product Approval Meetings in 2016 – By my count during 2016 there were 22 advisory committee meetings held to consider the approval of a new medicine. Last year there were 23 such meetings, though there was a much higher rate of drug approvals by the agency. That would indicate that a higher proportion of the new drugs approved by FDA this year had Advisory Committees than last year.
  • Rate of Approval Recommendations by AdComms in 2016 – Of the 22 meetings, the committee voted 19 times to recommend approval to the FDA for the new medication, and 3 recommendations against recommending approval;
  • Comparison of FDA Decision versus AdComm Recommendation – Of the 22 recommendations made by advisory committees, FDA ultimately went against the recommendation of the committee 4 times
    • In 3 of the 4 instances, FDA decided not to approve a compound where the recommendation had been for approval – in one of those 3 the vote had been a very close vote, in the other 2 the vote was split, but not close;
    • In 1 of the 4 instances, FDA decided to approve a compound where the committee had voted against the recommendation in a very close vote;
    • This year stands out a bit – the total of 4 decisions that were ultimately counter to Advisory Committee Recommendations meant that FDA went against the committee advice 18 percent of the time. In the August 2016 analysis looking at that question overall, it was found that on average FDA went against the advice of committee about 10 percent of the time.
  • Joint Committee Meetings – Of all the meetings to consider new product approvals, 4 were joint committee meetings of two committees. In all four instances, the candidate drug was seeking a pain indication and all involve the Anesthetic and Analgesic Drugs Advisory Committee with the Drug Safety and Risk Management Advisory Committee. In all four, the Advisory Committees recommended approval and FDA did approve three out of the four.

Technically, the year is not over. There are still 2 Advisory Committee meetings where recommendations were made and FDA has not made a decision. In fact, for a final tally of the year, of the 22 product considerations, there were 15 FDA approvals, 5 that were not and 2 still outstanding. That could alter the numbers related to the number of times that FDA went counter to an advisory committee recommendation.

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Look Back at OPDP Enforcement in 2016 – Focus on Pre Approval Communications

It was another year of low-level enforcement by the FDA Office of Prescription Drug Promotion (OPDP). In fact, if you added the number of letters issued over the past three years it would be one less than the number of the letters sent out for all of 2011.

That said, the 11 letters posted this year are a slight uptick over 2014 and 2015 do offer some interesting insights. But first, a general overview. Of the 11 letters:

  • 3 were Warning Letters, 8 were Untitled
  • All involved only a single communications vehicle (brochure, website, etc)
  • All but 3 of the letters went to pharmaceutical companies that fall outside of the top 50 by sales volume
  • The communications vehicles involved were primarily digital over print, with video being predominent
    • 6 involved video
      • 3 YouTube videos
      • 2 DTC Advertisements
      • 1 video
    • Of those not involving video the vehicles included
      • Email
      • Exhibit Panel
      • Coupon
      • Web page (2)
  • There were 20 violations cited in the letters for this year
  • The letters involved drugs in multiple therapeutic categories.

In virtually every examination of the violations cited in letters, the number one violation is always the minimization or omission of risk information. This year was no exception, with 7 of the 20 violations being in that category. The real point of interest this year, however, was in the number of letters issued for the promotion of an unapproved drug.

There were 4 such letters, which does not sound like a large number in and of itself. The Eye on FDA database on warning and untitled letters tracks letters through 2004 and contains over 300 letters and spans more than 1000 violations. In all that time, the number of letters involving the promotion of an unapproved compound were only 13 (all involving very small companies). That means that nearly one-fourth of all the letters issued for unapproved drug promotion in the last 12 years were issued in 2016, perhaps a signal that this has been a watch area for OPDP or that the agency has intended to make a point about it.

The issues that FDA cited in the letters had to do with a combination of factors including use of a trade name, referring to an indication and use of conclusory language or tone with respect to the establishment of safety and efficacy. You can view the 3 letters here, here and here.

Note: A typo was corrected after the initial publication of this posting to reflect 4 letters for pre-approval promotion rather than 3.

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