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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Regulation Cutting Impact on FDA and AdComms

During the campaign, candidate Donald Trump made several statements referring to the fact that he would be cutting regulation in this country by 70-80 percent. Since the election, that sentiment has been repeatedly affirmed.

Now in office, this week he signed an Executive Order that would require that federal agencies seeking to implement a new regulation must first do away with two.  The Executive Order also set an annual financial cap on the cost of new regulation and that stated for the rest of 2017, the cost of new regulation must be offset by the undoing of old regulations.

How might that impact FDA? Especially in the wake of the passage of the 21st Century Cures Act, there will be a number of regulations that will have to be devised and go into effect and the agency is still constructing the regulatory pathway for biosimilars. But the executive order issued by the Administration exempts rules and regulations that are being mandated by legislation.

Also this week in a meeting with PhRMA, Trump specifically indicated not only that FDA was included in the mix for regulation-cutting, but also that the approval process would be streamlined to shave significant amounts of time from the approval process.

The drive for fewer regulations has a potential for impact on a number of fronts. At least one of the persons being considered for FDA commissioner has stated that drugs should be approved once safety is established and that efficacy would be determined in the market place. In addition, it could mean that drugs that are under study have greater access for those patients who wish to try unapproved drugs, or “right to try” policies. Fewer regulations could also take the form of minimizing FDA’s role in conducting inspections of manufacturing facilities. Finally, when it comes to “streamlining the approval process” it could have a direct impact on the way drugs are currently evaluated for approval, specifically reform of the advisory committee structure and function.

A few days prior to his departure from FDA, Commissioner Robert Califf authored a posting on FDA’s blog (FDA Voice) entitled “FDA Advisory Committees: Independent, Informed, Essential and Evolving“- a title that tried to say it all – in which he outlined his thinking about the role of advisory committees. While the posting begins with a recognition that there is a common concern among medical leaders that the advisory committee system function be improved, the aspect that is discussed at length is process of evaluating advisers to serve and minimizing potential conflicts of interest.

But the advisory committee system has other issues, some of which are cumbersome. For starters, it is huge – just for human drugs alone there are 17 committees, each comprised of 10-15 people. Meeting logistics are involved, particularly if there is a joint meeting. The identifying, vetting and scheduling are enormous.

Then there is the burden of proof. A drug sponsor will have to compile an enormous amount of data and then have a very short amount of time to present it during a proceeding that may seem a combination of a scientific meeting and adversarial proceeding, examining both the safety and the efficacy of a compound. This may seem like a negative, but in fact (having witnessed scores of these meetings) they are very thorough which is something you the patient really want if you are staking your life on taking a medicine that is going to cure you of a serious illness or manage a chronic one. You want medicines held to a higher standard than supplements.

Needless to say, there are a good number of regulations associated with the delivery of a new medicine. The two-for-one rule is a very simple approach to a complex issue. Similarly cutting down on the scrutiny a drug candidate receives in order to get it to market faster may also seem like a simple approach to a complex issue. In both cases, in the end the outcome may not be what you were aiming for.

Ultimately the shape of advisory committees – and the faster speed of drug approvals – will not be determined for some time to come.  The choice of an FDA commissioner will likely shed a good deal of light on the direction, if not the timing. In the meantime, we are left to ponder three important questions.  First – if we were going to set aside 80 percent of FDA’s regulations – what would they be and where is the low hanging fruit? Second – is the means to getting rid of these regulations a sudden process, or the more gradual attrition by means of the two-for-one rule? And last, if we are not going to approve drugs by the system we have, what would a better system look like?

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What They Said in 2016 – FDA Releases

FDA ended the year quietly and began the new year in similar fashion. The holidays are of course a factor, but in all of October and November of 2016, there were only 3 releases issued for each month. Even in January, press releases were slow to start in the new year. In fact, from late 2016 until mid-January 2017, there were no press releases from the agency for a period lasting nearly one month – certainly the longest stretch in my time of observation. Despite the quiet, there has been lots happening – the subject of postings yet to come.

So the last quarter for the agency was not a highly audible one. That said, what did the agency have to talk about and how does it compare to other years? Time to take our annual look. First, here is an overview of how 2016 stacks up against 2015.

Perhaps first and foremost one can see that there were far fewer press releases in all during the year, but also that there were far fewer issued about approvals, particularly those for drugs or biologics – something noted in a posting in December. In fact, the drop-off in approval announcements is directly attributable to the significant drop in the number of press releases from 2015 to 2016.

Of the 32 drug/vaccine approval announcements, 22 involved new molecular entities according to FDA’s 2016 Novel Drugs Summary. The number of approvals for 2017 appears poised to pick up given that the report also states that there were 41 filings of BLAs and NDAs during 2016, leaving a fair amount for consideration in the coming year.

The other noticeable difference between the press announcements for this year and last is related to the issuance of rules. There has been recent observations made in the trade media that the number of guidance documents issued by FDA increased, perhaps a reflection of the agency wanting to get the guidance out prior to a new Administration. Not every guidance document is announced with a press release and in fact, some of the long-awaited guidance documents released in recent days (one on biosimilars, one on off-label) did not have accompanying announcements. In looking at the pattern over the year, press releases announcing a new rule or guidance occurred primarily in the first half of the year and was actually lowest for the final quarter.

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Additional Untitled Letters Issued by OPDP

It has been a rather extraordinary month for watchers of the Office of Prescription Drug Promotion (OPDP) in that while the office has issued very little enforcement during the bulk of the year, December has been making up for it. So far this month, there have been a total of 6 letters issued, 1 more than for the entire combined effort during the 11 months preceding December. And this month, they have come in batches of two.

As we have seen of late, both of the most recent letters issued on December 21 were sent to companies that fall outside of the top fifty pharma companies. Both letters involved videos posted to YouTube and both involved a single violation – the promotion of an investigative drug without FDA marketing authorization.

While the circumstances of the two letters bear those similarities, there are also differences. The first letter involves and investigative treatment for diabetic dyslipidemia and hypertriglyceridemia. OPDP cites claims in the video regarding the mechanism of action, claims about the benefits and that the compound “ushers in a new era”. In addition, there is a statement that the compound is indicated for its investigative purpose.

The second letter involves a compound that had already received a complete response letter (CRL). That is noteworthy because normally the agency does not reveal the contents of a CRL but in this case the company in question issued a press release which the agency did quote to say that the agency was looking for an additional clinical trial to firmly establish efficacy. In the video, OPDP cites direct statements made that are quite direct about the investigational compound being shown in trials to be safe and effective.

The central point related to violations involving the promotion of an investigative compound is to avoid statements in communications that imply either directly or indirectly that such a drug is either safe or effective. While the fact that both of these violations occurred on YouTube might reinforce a notion that social media platforms are inherently high risk, the violations would have been violations regardless of the communications platform. That said, it does bear noting that looking back through 2004 at the letters that have been issued by the office for promotion of an investigational compound, the overwhelming majority have been on digital platforms (mostly websites).

Most of us are on holiday hiatus and if you are one of them, I hope you are enjoying the holidays. In the meantime, given that Warning and Untitled letters often have a delay in being posted to the FDA site, we will hold off on a review of the entire year until after January 1. In the meantime, Happy New Year to one and all.

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Weekly Roundup 12.16.16

It has been a while since there has been a Weekly Roundup posting, primarily because FDA has been fairly quiet of late. In fact, during October the agency issued only 3 press releases and the same for November. Certainly lots is happening around the agency though, like the passage into law of the 21st Century Cures Act. This week we’ll have some things of note that the agency has done as well as a few updates on the changing environment.

  • FDA Announces Eczema Approval – It has been a year short on drug approvals compared to last year, but FDA added one to the list for 2016 this week in approving Eucrisa, a phosphodeisterase 4 (PDE-4) inhibitor being indicated for the treatment of mild to moderate eczema in patients two years and older. According to the company press release, there has not been a new prescription available for patients in over ten years. While overactive PDE-4 has been shown to contribute to the condition, the specific mechanism of action is not known.
  • FDA’s OPDP on the Move! – After a year that was relatively quiet on the enforcement front, Eye on FDA reported this week on two untitled letters issued by the Office of Prescription Drug Promotion (OPDP) related to DTC advertising and risk information. Then the following day a third and fourth letter was posted, this time both Warning Letters, also involving risk information (the most common violation cited in OPDP letters). This means OPDP has issued nearly as many letters so far this month as have been issued all year by that office.

That’s it for me this week. Have a good weekend everyone.

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