Enforcement Updates: OPDP Issues First Letter of the Year

In recent years, FDA’s Office of Prescription Drug Promotion (OPDP) has been diminished in the volume of its enforcement expressed through the issuance of Warning and Untitled Letters. OPDP now sends out only a handful of letters each year when it used to send dozens and dozens (see below for year by year breakdown). In fact, for 4 out of the last 5 years, the number of letters has registered in the single digits. The reasons for this drop have been the subject of speculation in the past. Perhaps compliance is way up. Perhaps it is a political decision. Or perhaps – more likely – it is a focus of resources. Rather than ferret out each and every violation it can find, significant or not, FDA is maybe looking to issue letters where it can make a point or make a difference.

Recent enforcement trends, such as they are, bear that out. In February the office issued a letter recently posted to the FDA site directed to a sponsor and principal investigator in relation to an investigational new drug. The agency took issue with a webpage where the investigational compound was the subject of claims and presentations that the agency said made conclusory representations when the safety and efficacy had not yet been established.

The letter follows two patterns out of OPDP. A feature of enforcement letters over the past few years is that they are predominantly directed at entities that are not household names – smaller pharmaceutical companies or in this case an imaging center (though last year did include letters to Pfizer and Eisai). But the second, and more significant characteristic is the violation that is being more often cited – for the promotion of an investigative compound.

In a review of the 330 letters issued by OPDP since 2004, a letter issued for the promotion of an unapproved drub has been the subject of only 18 letters – 5.5 percent of all letters. Those 330 letters covered over 1100 violations (letters typically cite more than one violation) which means that promotion of an investigative compound has comprised only 1.6 percent of all violations.

However, if you look at the proportion that this particular violation occupies in the past few years, it tells a different story. Fully half of all of the letters ever issued by OPDP involving promotion of an investigational compound have come out since 2016, comprising one quarter of all of the letters issued 2016-2019, or nearly 15 percent of all violations. Both numerically and as a proportion, actions regarding promoting an unapproved drug has risen substantially, signaling that this is a current enforcement priority for FDA’s OPDP. If you drop 2016 from the mix, the result is even more pronounced with one-third of the letters being about an investigational compound and comprising nearly one-fourth of all violations.

Risk information – either presenting it in a way that minimizes risk or under circumstances that omit risk information entirely – still is the most common violation, but clearly promotion of an investigational compound has the focus of the agency just now. So bear in mind, low enforcement does not mean no enforcement.

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Gottlieb Set a New Bar – What Happens Now?

The news that Dr. Gottlieb was leaving his post as Commissioner of FDA took everyone by surprise. Perhaps another surprise to many was the skill and judgment he brought to the job when initially he faced many critics due to his ties to the pharmaceutical industry. Yet of the many names floated at the time for the post, he was clearly the most qualified – offering the perspective not only of a doctor, but as someone who fought cancer, as a patient as well. And he brought experience. He was not new to FDA having served as a Deputy Commissioner under Mark McClellan. During that time, one would imagine that he devised a blueprint for how he would do the job were he Commissioner. When he actually became Commissioner, he went about implementing that blueprint.

But while detractors expressed concern over pharmaceutical company ties, as Commissioner it became apparent that what you saw with Dr. Gottlieb was what you got. Over the years as a Resident Fellow at the American Enterprise Institute he wrote extensively in national publications opining on a number of themes that were ones he would eventually bring to the job. In the grand picture, he looked at an agency that some may have said had become so entrenched in process that it lost sight of the goals for which it existed. The idea that everything should be done according to the same process it had always been done challenged progress. He embraced mechanisms that might loosen that up. Many of the policies that came about as FDA Commissioner he wrote about as themes in the years before.

For example, the idea of rolling submissions of BLAs and NDAs offered a means for companies to make progress in the development of new drugs at a faster pace. The tenure of Dr. Gottlieb as Commissioner is characterized by the notion that resources were best used in a way that maximized impact when it came to development and in the area of safety, focused on those areas where there was the most risk, rather than spread resources evenly across the risk spectrum. To that end, across a broad spectrum of development, there has been change effected in the way the agency is going about its business – from the faster development of generic drugs to new heights in the approval of new molecular entities.

Also during his time at FDA, the agency oversaw approvals of huge steps forward, particularly in oncology.

He has also not been shy to tackle large issues – vaping among youth and the opioid epidemic.

Moreover, he has not kept what he was thinking and doing a secret. Dr. Gottlieb is someone I’ve known for a long time and he always liked to talk. But as Commissioner, just as he did during his days at the American Enterprise Institute where he frequently published his opinions and ideas, he continued to do so through the issuance of “Statements from the Commissioner”. These were not one-offs. Rather there were topics, such as the development of a response to the opioid epidemic to the pursuit of more generic approvals to the development of pathways to speed the regulatory oversight over the approval process for new therapies, whereby he marked progress and communicated to stakeholders not only what was happening, but much of the reasoning behind it. Whereas past commissioners relied on a more reactive means of communications – providing updates during Congressional testimony and speeches for example, he took more of an initiative to be proactive. In doing so, he did it not only broadly speaking – on a range of topics, but with depth as well.

All of this changed what we have come to expect of someone heading FDA. The question becomes – now what? As he leaves the office, he demonstrated that one can have vision, ideas on how to execute that vision, and ability to do it when needed, all the while communicating transparently about it. He came to the office having had a long time to think about the role beforehand and he was effective in making change that had a positive impact. In addition, he is a snappy dresser. One hopes there is a similar presence that can keep the bar where it has been set.

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In the Pharma Pricing Debate, We Are Talking About More Than Apples and Oranges

This week the Senate Finance Committee held the second in what will be four hearings on the price of pharmaceutical drugs – Drug Pricing in America: A Prescription for Change. The first hearing, on January 29, listened to a panel of patients, patient advocates and academics, while the second invited the leadership of seven major pharmaceutical companies. In addition the House Oversight Committee on Government Reform held its first hearing of the year also on the topic on January 29, the same day as the first Senate Finance Hearing. Early in the year, Senator Mitt Romney reportedly told pharma execs behind closed doors that “change is coming” – similar words uttered by Senator Menendez at the close of the second Senate Finance Committee hearing. More talk is to come.

But in viewing both Senate Finance hearings, to the ear of someone who pays attention to communications, it becomes clear that at least part of the problem has nothing to do with rebates, or couponing, or any of the mechanics of pricing – it has to do with communications – what it is people are talking about. It boils down to three things – there is price. Then there is value. And finally there is cost. Stakeholders are speaking from different corners. They are oil, water, and something in-between. And they don’t mix very well.

Price. Patients are concerned about price. Patients, after all, are consumers before they were patients. As a consumer, you walk into a store and you see an item and you assess whether or not you want to buy it based on the price. If there is a comparable item at a lower price, you are likely to opt for that. If it is on sale, that is also a big factor. You expect that the store owner and the manufacturer are going to get a cut, and earn a profit, and you accept that as fair.

But when you are a patient, it is different. In the end, the patient perceives the medicine as it would any other commodity – like buying a new smart phone. He is willing to pay a premium price for the newest thing, appreciates that investment goes into developing the technology and expects that expense is written into the expensive, but ultimately affordable (for most) price. And above all, no one expects that they will have to ration food or paying utilities in order to buy a smart phone, the way that some patients testified in the Congressional hearings that they must do for medicine.

Value. Then there are stakeholders, like industry as well as organizations that assess price who consider the value that a treatment brings to the patient and to society as a whole. An example used during the second Senate Finance Committee hearing was in the treatment of Hepatitis C. Prior, many patients with this condition had to eventually undergo liver transplants – an intervention costly in many ways, but especially dollars. Therefore, a new medicine that brings a cure and thereby circumventing thousands of dollars in costs to everyone should be priced at a level that reflects that value. So if we are saving $50,000, a $25,000 price tag reflects the value that the treatment brings to the table.

The problem of course is that when there is a high price tag, many patients will have a hard time – high co-pays, high deductibles, mean high out-o-pocket costs. If it is a treatment for a chronic condition, this means high on-going costs. And the message to patients, who are thinking price – is that everything is being valued except their own well-being. It becomes a “your money or your life” proposition.

Cost. And here is where it gets a little murky. To address the situation, there are a whole set of mechanisms to adjust the amount that will ultimately be paid by the patients. There is the list price, the direct price (DIRP), average wholesale price (AWP), there are rebates, there is the wholesale acquisition cost (WAC). You practically – well not practically – you do need a guide for this part. There are enough acronyms to have the person of above average intelligence (PAAI) confused, frustrated and feeling like something is going on. And this is the part where pharmacy benefit managers (PBMs) come into play. For patients, these are faceless entities. They are also likely the subject of a future Senate Finance Committee hearing on pharmaceutical pricing.

When talking about this issue, each stakeholder is speaking a different language. Smartphone patient price perception is confronted by real estate value model and complicating it all are an entity we never see with a lot of confusing language.

In the end, what we have here is communications problem on top of the problem in our approach to this marketplace. This is one of those classic communications situations where many of the stakeholders are so focused on what they need or want to say, they are not taking into account what their audience needs to hear. One the one hand, if we are going to solve the problem, we have to make sure everyone not only understands the problem. But perhaps more importantly, if we are going to make real headway, it is not so much about government hearings spouting hyperbole, but rather taking into account who our audience is and what they value – determining what they need to hear and addressing it in the course of the conversation – that will ultimately bring about a more satisfying outcome.

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FDA’s Contribution to the Pricing Issue – Generic Activism

As hearings on Capitol Hill these past two months (and in the months to come) have examined the issue of pharmaceutical pricing to inform potential legislation as well as to garner attention, FDA has been addressing the issue in the only way the agency can, through policies that enhance the development of generic and biosimilar competition for brand name drugs. In fact, in 2017, FDA approved a record number of generics – 1000 – a record the agency broke in 2018. Overall, the effort at promoting the development of generics as a means of addressing price has not only been assiduous, but wide in scope.

For starters, on Friday, February 22, the agency announced that it was releasing 74 product-specific guidance documents, 49 covering complex drugs, including 16 for which there are no approved generics with the aim of supporting approaches to developing new generics. It is one of many examples of how FDA has sought to move the needle in the generics market place. This is at least in accordance with a statement from the commissioner made after a GAO report released in early 2018 recommended that FDA revise its guidance documents on complex drugs.

Much of the activity is related to the fact that in May of 2017, FDA announced its Drug Competition Action Plan. Almost immediately thereafter (in June) published a list of off-patent, off-exclusivity brand name drugs that did not have competition as well as implementing a policy to help expedite review of generic applications. In that same announcement the Commissioner stated that FDA would expedite the application for a generic drug until there were three generics available for a brand product. In July of that same year, the agency held a hearing to identify where there were ways for the agency to enhance generic development.

In between the announcement of the Drug Competition Action Plan and the product-specific guidances, there was a good deal of other action announced or taken by the agency:

  • Policy Change – On the occasion of the release of the Trump Administration’s blueprint for addressing drug pricing, FDA issued a Statement from the Commissioner in which he reiterated the agency’s commitment to making an impact in the process for approving generics and in calling out “gaming” practices that might delay competitive generics in market entry and a few days later announced that the agency would be publishing a list of companies. In January of this year, the Commissioner issued a statement to signal the coming issuance of new policies to support generic entry into the market for complex drugs;
  • Funding to Facilitate Generics – On February 13 of last year, FDA sought additional funding to, among other things, modernize generic drug review from text-based to data-based assessment. And in July announced the formation of a work group to examine a policy framework to look at importation of drugs address situations where there is only one U.S. approved and marketed version of an older drug that may not be commonly used, but is medically important and often involving generic medicines.
  • Gaming Practices – Last Spring, the Commissioner announced steps on one of the issues touched upon in this week’s Senate Finance Committee Hearing on drug pricing – the “gaming” of the system to delay generic competition. The agency began publishing a list of companies identified as potentially blocking access to samples of branded products. That same month – also in a Statement from the Commissioner – FDA announced new policies to reduce the ability of brand drug makers to use REMS programs as a means to blog generic market entry. In October the agency announced new options to further curb “gaming” of the process by revising a draft guidance regarding the use of citizen petitions to add a resource burden to generic review process.
  • Expedited Approval Pathways – In August the agency announced the first generic approval under the Competitive Generic Therapy designation – a new approval pathway created to expedite the development of new entries into the market where there is a lack of competition, formalized in an announcement this month and defined as a pathway granted to a company submitting an application where there is not more than one approved drug in the Orange Book. In October of last year in a Statement from the Commissioner new guidance documents were issued to advance the development of generic transdermal and topical delivery systems with the aim of enhancing the development of generic versions of complex drugs.
  • Safety – This month, in the wake of media reports regarding the questionable quality of some imported generics, the Commissioner and the head of CDER announced steps regarding the oversight of safety and quality issues related to both domestic and imported products

As an agency, FDA has a narrow band-width in which to operate when it comes to the drug pricing issue. But within the space it has, the agency has been very active and very comprehensive. In fact, if you look for the word “generic” in the headlines of agency press releases between 2013 and 2017, you will find almost nothing. If you look at it in the past few years there are at least a dozen. If not activist, the agency has certainly been active.

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Sorting it Out – FDA AdComm Review for 2018

Looking back at FDA Advisory Committee meetings (AdComms) held during any given year requires a bit of patience given that some of the approval results don’t come in for a while after each meeting is held. And in fact, there are still some drugs that were considered by advisory committees during 2018 for which there is still no FDA decision. But we are going ahead with a look-back anyway.

FDA holds advisory committee meetings in order to get input from experts and from the public regarding the approval of new products and has a fleet of advisors serving on those committees. For Human Drugs there are 18 committees with varied subject matter jurisdiction. Not every new drug application goes through the advisory committee process, but for those that do, from a communications perspective, it is often where the branding of a medicine takes its first breath.

That is because when there is an advisory committee meeting held it does bring more transparency to the approval process because there is a publicly open scrutiny of the application. This, in turn, has communications ramifications. While the application milestones and clinical study outcomes have largely been public, the bulk of attention has been paid in trade and scientific journals. When there is an AdComm, there is a shift to mainstream media coverage. And while the filing of the new drug application and the acceptance of that application are important milestones, it is when FDA posts the briefs of the professional reviewers within FDA that result in headlines in mainstream media. And because reviewers are citing their perceptions of the strengths and weaknesses of the drug in question, the comments in those briefing documents generate the first real round of headlines about the medicine. The second wave comes as a result of the meeting discussion and vote. And as we know, the vote is a recommendation to FDA which the agency may or may not follow.

All that said, how did 2018 stack up in terms of Advisory Committee activity and how did it compare to the year before? Last year, FDA approved a record number of new molecular entities (59). In addition there were approvals of biosimilars and approvals of drugs that were not new molecular entities, as well as label expansions.

More Meetings. There were more meetings held last year than the year before. In all there were 34 meetings of advisory committees last year, but only 27 of them involved the consideration of New Drug Applications (NDAs) or supplemental New Drug Applications (sNDAs). That is slightly higher than last year when there were 29 meetings, 23 of which were considering NDAs for approval, two of which ended up not taking place.

Most New Treatments Considered. In 2017, the Oncologic Drugs Advisory Committee came in at a whopping 9 meetings to consider drugs, but in 2018 met only once. The committee with the most meetings in 2018 was the Analgesic Drugs Advisory Committee with 7 meetings, indicative of the activity around pain. Also in 2018, the Antimicrobial Drugs Advisory Committee met 6 times.

Voting Patterns/No Votes. In 2017, the Committee that had the highest number and proportion of negative outcomes was the Arthritis Drugs Advisory Committee, voting down 2 out of 3 NDAs, while in 2018, it was the Analgesic Drugs Advisory Committee that voted down 2 out of 7. In 2017, the Advisory Committees voted to recommend approval 71.4 percent of the time; in 2018 it was 66.6 percent.

Disagreement in Outcomes Between FDA and AdComm. As is noted in every press release about an AdComm vote, FDA may or may not follow the recommendation of the committee. That naturally raises the question – how often does FDA go against the advice of an advisory committee. Consulting my own database that tracks outcomes, I have found that FDA goes against the advice of the committee about 11 percent of the time. In 2017, there were 21 recommendations and FDA went counter to the recommendation of the committee in 3 of them (14 percent). In 2018 there were 27 votes and FDA appears to have gone against the recommendation 4 times (15 percent). There is still one FDA decision still pending where FDA has extended the PDUFA date for the investigative treatment for postpartum depression Zulresso(TM) from Sage Therapeutics. If FDA’s decision ran counter to the AdComm recommendation of approval, would change these numbers slightly.

For your reference here is a table comparing the activity of the past two years. The first column denotes the number of meetings/medicines considered by each committee, the second the number of approvals voted, the third the number of times FDA had a different outcome from the recommendation.

Comparison of FDA AdComm Activity 2017-2018

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