OPDP Sends First Letter of 2017

To put it mildly, enforcement by the Office of Prescription Drug Promotion (OPDP) has been lagging. Warning and Untitled letters from this office numbered in the triple digits twenty years ago. In the past three years, it did not break a dozen. Last year was poised to be the lightest on record, but in December OPDP suddenly came forth with several letters within a month. In the five months since, there has been an overwhelming lack of activity.

Today there was a blip. OPDP posted an Untitled Letter for a DTC Broadcast television advertisement to market a drug with an indication for weight loss. The letter noted that the drug has several warnings and contraindications noted in the label which also includes a boxed warning. In issuing the letter, the only violation that was the subject of the FDA’s enforcement was with regard to the minimization of risk information, which is by and far the most common violation of any cited by the agency when issuing such letters.

There are two issues with respect to risk that are of note. The list of contraindications spans a number of conditions and situations as well as a number of potential adverse reactions. FDA asserted that while contraindication was included as part of the ad, the full spectrum was not present. While there was a statement that the product was not something to be considered for use by everyone as well as one stating that “other side effects may occur” such umbrella statements were not deemed sufficient by the agency to cover the range of risks and contraindications from the label.

In addition, there was an issue with regard to risk presentation. In a March blog posting we looked at DTC advertising and some of the risks associated with it in light of research FDA has undertaken with regard to how risk is being conveyed. Specifically the agency has been on the hunt for anything that might compromise clarity and therefore comprehension on the part of the viewer. Here, among other things, the agency took issue with important risk information being conveyed visually while competing material is being conveyed orally.

The issuance of a letter involving a DTC advertisement is another indication that OPDP is still more focused on traditional communications vehicles than it is emergent digital platforms.

Two questions unrelated to the contents of the letter may naturally arise in the wake of this letter.

First – does the issuance of a letter after a five-month silence indicate a renewed effort at enforcement following the change in leadership at FDA?  Since these letters take a good deal of time to generate and the change in hands has occurred only recently, that is doubtful. Also the flurry of activity in December did not indicate more letters forthcoming in their wake.

And secondly – why has OPDP had such a downturn in enforcement? The agency has stated that there are other forms of enforcement activity besides the issuance of letters, but provided no clue as to what that might be. Lacking transparency in that regard, the only quantifiable means we are left with is the issuance of letters. Stay tuned.

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How Much Change Does a Commissioner Make?

For the second time in as many years, we have been going through the ritual of getting a new FDA Commissioner appointed. The last one – Dr. Robert M Califf served from February 2016 until January of this year. Dr. Scott Gottlieb was nominated by the current Administration in March to be the new head of FDA with hearings in April.  Yesterday the Senate confirmed Dr. Gottlieb as the new FDA Commissioner by a vote of 57 to 42.

An inherent component of the deliberation process is a focus on how the nominee might influence the future direction of the agency itself. During Dr. Califf’s nomination process, there were concerns raised in the Senate about ties to the pharmaceutical industry, a concern that repeated itself this time around regarding Dr. Gottlieb’s experience as a consultant and board member for several companies. The focus of concern is, of course, what influence will such ties be on the conduct of an FDA commissioner and on policy itself?

FDA Commissioners can obviously set priorities and direction in ways that will influence policy for the agency. For example, Dr. David Kessler, who served under both Presidents George H.W. Bush and Bill Clinton, had a long tenure. One of his many contributions involved efforts related to the regulation of tobacco products. Dr. Margaret Hamburg who served under President Obama took over the helm of FDA during a time when the agency had been very battered by a series of events that included high profile drug recalls. Her background and experience as the Health Commissioner for the City of New York among other things positioned her well to see to administrative reforms that restored confidence in the agency.

While the influence of an individual person obvious impact, outside events – or the demands of the time – have a much greater influence on the policies and actions of FDA. The agency is not just a big ship to steer, it is a really, really giant ship. It does not turn on a dime. It regulates not only a huge breadth – food, drugs and cosmetics – but with a very big depth. In the case of medicines, for example, this means shaping the kinds of clinical trials needed, the specific endpoints to shoot for, an enormous mechanism for approval and oversight of manufacturing as well as marketing. Change does not come easy to such a big system of regulation – it is definitely a process, not an event.

When FDA does make dramatic change, external events are the most likely driver of that process. Prior to the HIV/AIDS epidemic, approval times for drugs ran many months longer than they do today. Policymakers responded and FDA instituted reforms that resulted in Fast Track and Accelerated Approval and today the options for enhanced approval are numerous. The emergence of biosimilar medicines and the more rapid assembly of a regulatory pathway for their approval and use in Europe again moved Congress into action to create legislation that would authorize new regulations. There are numerous examples.

There are many pressing issues in medicine right now. From pricing issues (FDA does not involve itself in pricing) to the faster approval of generics to promises by the Administration to reduce the regulatory burden involved in drug approval. There are new emergent and successful classes of drugs that involve immunotherapy, personalized medicine and the press for an enhanced pursuit to find answers in cancer. These issues as well as others will undoubtedly shape the agency. But when it comes to how the FDA does its work, it is the presence of pressing issues, and the actions that policy makers take (such as passage of the 21st Century Cures Act) which will have the most lasting impact on the direction of FDA as he faces the large array of external events that will drive change over the next several years.

Other candidates under consideration for FDA Commissioner included some who did not have medical degrees. The choice of Dr. Gottlieb, who holds a medical degree, is a cancer survivor and has experience as a former FDA deputy commissioner, likely signals an acknowledgement on the part of the Administration that the complex questions of the time need experience, understanding and pragmatism to help shape the agency response in meeting the demands of today’s environment for medicine. The fact that he is doctor, patient and experienced administrator in a single person are likely the more important traits that will influence his tenure at FDA.

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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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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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