New Drug Approvals – A Mid-Year Assessment

During the past few years, there has been a renewed focus on facilitating the development of new medicines by providing new mechanisms to streamline the review process and get drugs to patients more quickly. The passage of the 21st Century Cures Act and its implementation by the Food and Drug Administration has aimed, among other things, to speed innovation with the aim to bring more treatments to patients more quickly without compromising FDA’s safety standards.

Has it worked? At first blush, there has been tremendous output in terms of new drug product approvals. In 2015, there were a record 45 approvals of new molecular entities, followed by a dip in 2016 to 22 (the 21st Century Cures Act was signed into law in 2016). In 2017 it went back up to 40 and last year we saw a whopping 59 approvals.

But so far 2019 is not shaping up. After the half of the year, we are only at 13 approvals, or on average a little over 2 a month, compared to the 2018 when there were 20 approvals by July 1.

How does mid year 2019 compare to other mid-year tallies? Actually not so good. While it would appear to be lagging – certainly far behind mid-year of the past two years – it is actually not far behind 2015 which was a record-setter by the end of the year, indicating that a mid-year assessment is not always a very crystal ball regarding the rest of the year. In 2016, for example, there were 14 approvals at mid-year, but only 8 over the following 6 months. The year before there were also 14 at mid-year, followed by 31 during the last half of the year. So one might think that there is at least a chance this year will pan out.

But, looking at a couple of indicators might dampen the spirits.

Advisory Committee Meetings – AdComms are down. The first indicator of how we will fare over the next six months is a near-term one and not a wholly practical one. Advisory Committees are not scheduled for every new drug approval. But it is still a factor and right now, it is one that is running low if you consider how many advisory committee meetings are scheduled as of now to consider new NDAs. These meetings are usually scheduled about 6 weeks out from the date of the meeting. Currently, there are only five advisory committee meetings scheduled to discuss drug approvals in the coming months, and one of those is an sNDA. One other point about advisory committee meetings, FDA has only held 9 so far this year to consider new products. By this time last year, the agency had held 16.

PDUFA Dates – That leaves us with PDUFA dates – certainly the more informative indicator. PDUFA dates are the date by which FDA will announce a decision about a new drug application, which may or may not be a new molecular entity. PDUFA dates are generally proprietary and there is no way to absolutely know all of them if companies do not choose to divulge the exact date. That said, many companies either do explicitly state their PDUFA date or at least give a ballpark idea by the date that specific announcements are made by press release.

Tracking PDUFA dates from year to year then is an inexact effort. That said, by my count there are a total of 108 PDUFA dates for the entire year of 2019, compared to 119 for 2018. Of the 119 in 2018, at least 78 were for NDAs (as opposed to sNDAs), meaning that this number could include NMEs, compared to a total of 61 NDA-related PDUFA dates in 2019. Of the 61 NDAs PDUFAs for 2019, 29 of them have dates that have passed, leaving only 32 possibilities. And finally, if all 32 were NMEs, which is not the case, that would still leave us short of last year when combined with the 13 approvals during the first half of 2019. By contrast in 2018 by mid-year, there were still 44 PDUFA dates left.

All in all, if you are looking for a banner year, this may not to be it. And if the numbers remain low, it may call into question for the true impact of the 21st Century Cures Act. Time, and transparency, will tell.


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OPDP Sends Third Enforcement Letter of the Year

The folks at the Office of Prescription Drug Promotion (OPDP) have been in the mood lately to make a point. You can tell because they recently issued the third regulatory action letter of the year. Many years ago this would have likely occurred by early January. Now it takes half the year. With so few letters issued, when they do send one out, it seems geared to make a specific point.

The most recent missive went to Aclaris Therapeutics.  It is the first letter for the company and it was an Untitled Letter dated June 14. This is also the third Untitled Letter – no Warning Letters so far this year. The communication that was the subject of FDA scrutiny this time was a “direct-to-consumer video of an interview” that featured two paid spokespeople of the company, one of whom was a physician. The two missteps that were cited by OPDP were a misleading risk presentation and misleading claims about efficacy.

Pertaining to the risk issue – as part of its scope, OPDP engages in a good deal of research. In 2017, OPDP completed a research project entitled “Disclosure Regarding Additional Risks in DTC Prescription Drug TV Ads” (results published here) and in 2018 a project entitled “Impact of Ad Exposure Frequency on Perception and Mental Processing of Risk and Benefit Information in DTC Prescription Drug Ads”. It is difficult to say whether this body of research had any bearing on OPDP’s enforcement action, but the office has certainly been highly focused in its research on various aspects of DTC.

First some background on the product – a topical solution to treat seborrheic keratoses that are raised – comes with several warnings and precautions in the PI, with the most common adverse reactions being erythema, stinging, edema, scaling, crusting, and pruitis.

Now FDA’s beef with the communication. The video, OPDP stated, featured a discussion between the spokespeople where benefits and claims associated with product use were made, but without prominent, balancing risk information reflected in the warnings and precautions portion of the PI. OPDP noted that viewers were referred by the physician to Eskata.com for more information and that the video included superimposed text listing the most common side effects, but omitted specific mention of the most serious risks was omitted. It would seem that the effort to direct viewers to the information on the website was insufficient, much in the same way it is for written copy to incorporate risk information by link.

This was compounded in the eyes of OPDP when the physician spokesperson made the statement to the effect that after one or two treatments, the condition resolves “and that’s the end of it” though some patients experienced adverse reactions for a long interval than after application of the medicine. And finally, placing common side effects in SUPERs that run simultaneous to compelling claims makes it difficult for consumers to process the content.

The same phrase noted above – “and that’s the end of it” – was also cited as the basis for the efficacy concern OPDP had. The statement had been accompanied by photographs of two patients that were before and after in nature. However FDA did not consider that these depictions portrayed a typical response that would be derived from the clinical studies.

Picking out specific patients to portray outcomes may be almost ask risky as having patient testimonials. With testimonials a portrayal regarding outcomes from treatment are naturally often subjective in nature and it is easy for a patient to characterize their experience in a way that departs from what the norm might have been. Similarly photographic images of patients can also end up being subjective if they do not capture the absolute typical response to treatment for patients broadly.

OPDP has curtailed the issuance of enforcement actions, focused primarily on those situations that provide them with an opportunity to make a specific point or where there is a specific concern regarding public health. This feels like the former. And the bottom line lesson is that it is clear that risk information cannot be incorporated by reference or by direction to a website and that balance cannot be achieved in a video through super scripting that runs while the viewer is visually digesting other, and maybe even competing, information.

That is three letters in the first half of this year. It is impossible to discern how many more the year will yield, but it can be relied upon that you will find a write up here.


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OPDP Takes Second Enforcement Action of the Year

This week FDA’s Office of Prescription Drug Promotion (OPDP) posted what was only the second enforcement letter of the year which was issued in May. Warning letters are issued by many parts of the FDA, but OPDP issues letters squarely aimed at the communication by pharmaceutical companies about the medicines they market. Twenty years ago such letters were issued with ferocious frequency, numbering over 150 at their peak. So far this year, there are two.

At least part of the reason for the drop-off has been a change in focus by the agency to be more risk-based in the expenditure of time, resources and effort – something former Commissioner Gottlieb felt strongly about. That has extended to OPDP which used to issue a letter for a technical infraction of communications boundaries that would not have really had an impact from a public health perspective, but are more prone to act now only where the agency sees infractions that are violations where there is a potential for some kind of harm.

That has meant, as noted here in past postings, that there has been a concentration on two types of violations. First, the presentation of risk information. And second, a focus on the promotion of unapproved products.

The most recent letter falls in the former category. There are two types of letters – Warning Letters reserved for situations FDA regards as more serious, and Untitled Letters for those considered less so. The letter issued this week was an Untitled Letter, sent to VIVUS for website content for the weight loss drug Qsymia. The letter was issued almost 15 years to the day that the company received their only other letter from OPDP (then DDMAC) back in 2004.

The letter regarding the Qsymia website addressed the presentation of benefit and risk information related to the product. Noting that obesity is an extremely common condition for which people are seeking help and that the drug itself had several limitations associated with its use and serious potential risks, the agency took issue with the balance between the benefit information presentation versus the placement of the risk information on the site. In addition, a claim that the drug worked three times faster than diet and exercise alone was cited by FDA as being a claim that was without support because the data cited for support calculated the amount of weight lost, but not the rate of the weight loss itself.

In addition to the risk information, OPDP addressed the treatment of benefits for the drug. The agency said that the patient data utilized in the discussion of benefits did not factor in the substantial number of patients who withdrew from participation in the clinical trials, which the agency deemed a selective presentation of results that resulted in overstating efficacy.

As stated above, this is only the second letter of the year. The prior one was directed at communication deemed to be pre-approval promotion. These are the two areas which seem to be the focus of the agency. While this letter dealt with obesity, the prior letter dealt in a product used in imaging related to treatment of oncology patients. Neither product had a boxed warning on the label, meaning FDA’s focus on areas where they consider a health implication to the violation is not confined to products with such labels. By OPDP standards, the year is still young and it is possible we could see more letters this year, but look for them in areas of risk information and promotion of an unapproved drug or use.

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A Look at the FDA Revamped the Website


It has been a long time since FDA did much to its website. Being such a large and diverse agency, managing the site cannot be an easy thing. Aesthetics apart, just keeping track of pathways and names can be overwhelming and it is easy to lose track of what needs to be updated when things change. For example, one pathway to get to Warning Letters from the Office of Prescription Drug Promotion (OPDP) still listed that office by its former name from changed in 2011, the Division of Drug Marketing, Advertising and Communications (DDMAC). In addition, there were multiple pathways to get to some information. The information regarding advisory committees might seem straightforward initially but when one began navigating it, it was anything but.

But FDA has attempted more than just putting its (website) house in order, it also remodeled not only functionality, but the way it looks as well. The new site is much cleaner – the layout is far less busy and crowded and the look is much more contemporary. Just the other day I was wondering when they were going to get rid of that tired old picture of an advisory committee meeting and poof, it is gone.

So I am not a website expert, but I do work in communications and of course, am a frequent user of the site. Here are some takeaways:

  • User/Consumer Friendliness is Improved – FDA stated that one of the goals was to make the site more friendly to consumers and it certainly is an improvement. While the former site ran banner photos of some topical interest, the new site landing page features a topic with a large photo array that is focused on a feature topic. To get to the information, you need to click on the box announcing the feature, not the photos. Key to success for this approach will be topics that change out frequently as well as the topics themselves. This month’s is about children and allergy relief. Certainly topical given the time of year and the number of children, but perhaps not as serious as the recall of blood pressure medications. This approach may be more consumer friendly than the old site for sure, but the execution will tell just how much so. In fact, each division – Drugs, Food, Medical Devices has “featured information” that generally mirrors the FDA landing page (though stylistically there is not consistency across all divisions in terms of layout). For FDA to achieve its consumer friendly goal here they will have to work at providing information that is of interest to consumers and not necessarily just focus on that information FDA wants most to talk about.
  • Longer, Less Crowded Landing Page – It used to be when you went to FDA’s landing page, you had a LOT of information crammed into the screen offering you pathways in a bunch of different directions at once – from links to speeches to advisory committee information to meetings information to the latest press releases, etc. All of that is still on the landing page, but it is more coherently laid out. That means that there is less splashed in your face on the screen, but the content has been elongated – and you now have to scroll down to find all the bits and pieces. That may not be entirely apparent to some. As you scroll down, you come to additional featured topics beyond the main one mentioned above. Right now one of them includes a link to information about the revamp of the site; a link to information about combatting opioids and one on FDA fostering drug competition. As noted above, these topics fall a little more into the category of things FDA may want to say versus the things we want to hear more about from a consumer perspective. As you scroll down, you come to press announcements (where curiously the title of the section is in smaller type than the titles of the most recent press releases). Scrolling down further takes you past many of the links that were formerly crammed into the landing square of the old site. It is almost all still there, just there more for your leisurely scrolling rather than in your face. But not everything is on the landing page. For that you need the next section.
  • Menu Function is Key – In the upper right hand corner is the Menu Function. You are going to need this as it is the key to providing you a one-size fits all access to various divisions of the agency. It takes you to a site-map-lite that is actually very helpful if there are some specific things you want to look up. Most notably on the left side are a list of “featured links”. These are vital. They take you not only to guidance documents, but also one is the link that gets you to Advisory Committee information — to the page that is set up for each committee containing such information as the committee roster and meeting notices as well as documents related to specific meetings. To the right of this menu you will also find access to the FDA’s divisions, though it is not called that – instead it is called “Products”. Under that heading you will not see links to “CDER”, “CBER” or the others and where is the Office of Prescription Drug Promotion? Actually CDER, CBER and the others are there, but they are not called that. They are under their generic names (haha) – Drugs, Food, Medical Devices, Radiation-Emitting Products, etc. FDA may want to consider adding the acronyms here. These pages are generally laid out in similar fashion to the initial agency landing page, with a heading that is meant to cover topical information, prompting the user to scroll down to find the bits desired. Here you will find a link as you travel down the page to the Warning and Untitled Letters issued (still only one issued this year so far). The link to the Office of Prescription Drug Promotion exists but not on this page – it is under the About FDA Tab, and then drilling down through organizational structure through CDER there before you find it – here.
  • Finding Specifics Related to Function in the About FDA Link – One thing you don’t see when you go to the Drug page or the Food page or any of the other division pages is a map for getting to where you want to go within that division (hence the lack of an OPDP link from the Drugs Page). To find that level of detail – to find a specific office that does a specific function, you may have to either conduct a Search (which can offer up a messy slew of links) or go to the About FDA link mentioned above. Here’s the thing – that is in very small letters at the very bottom of the landing page. It is a small, obscure link to an important function. They may want to think about elevating that one up to the top of the page, and making it a little more prominent.

All in all, as noted above, it looks a heck of a lot better and the navigation is less confusing now that everything is removed from a single frame shot. The order of things as you scroll down is pretty logical, though the demarcation of sections is subtle. It was certainly due for a change. Of note, if you have links to FDA materials at any site, some of the material may have shifted. On my own tab on Social Media and FDA, the guidance links appear to be in tact, but other links will need to be updated.

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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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