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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Posted in Approval Announcements, FDA Image, FDA Policy | 1 Comment

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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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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