Update on FDA Approvals for 2019

Last year new molecular entities (NMEs) were approved by FDA at a record clip, surpassing the prior record of 45 that was set in 2015. As we begin the final quarter of hte year, this is a good time to check in on how we are faring in 2019.

It may have been tempting to attribute last year’s spike in approvals to the passage of the 21st Century Cures Act (the Cures Act), pointedly designed to facilitate and speed up innovation and new drug, biotech and device approvals. But the implementation of an Act as broad and deep in scope as the Cures Act takes time. Any credit to the Cures Act for the increase in NME approvals may have been premature.

In a mid-year check up posting for this year, it was noted that approvals of NMEs at FDA was running far below the pace at which it was the previous year and that the number of known PDUFA dates for NDAs and BLAs (versus sNDAs and sBLAs) appeared to be lacking in number to make this year equal or surpass last. With less than three months to go before 2020, the news from the third quarter is that nothing has changed. Comparing approvals by the end of the third quarter of each year, one can see that we are in line with 2015. That would not seem to rule out the fact that we could still have a good year.

At the mid-year mark earlier this year we were at 17 NME approvals. Having added 10 new approvals in this quarter, the pace has certainly picked up. An approval rate like that for the last quarter would certainly bring this year into line with 2017 and 2015, but still far short of last year. What does the 4th quarter look like?

That leads one to look at known PDUFA dates that are upcoming to see if there is a well upon which to draw for future NME approvals this year. While proprietary, I track PDUFA dates in a database as they become discoverable or can be estimated from public information. By my count there are 33 dates for this quarter for FDA decisions on submissions, which suggests a big potential for approvals of NMEs. But two things – first not all submissions are for NMEs, thereby narrowing down the possibilities. The second thing is that of those 33 dates, only 18 are for NDAs or BLAs, and only 4 are priority reviews, suggesting that there is perhaps not a deep well of NMEs available.

Time will, of course, tell. But as one attempts to interpret the true impact of the 21st Century Cures Act, the fact is we may have to wait a bit longer to realistically assess its benefits, at least as far as new approvals and innovation are concerned.

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Enforcement Update – FDA OPDP Sends Two More Letters

For those who like to keep up on the activity of the Office of Prescription Drug Promotion (OPDP) here is an update. While not shaping up to be another big year of enforcement, there has been a bit of activity lately that merits a look. So far this year, there have only been a total of five enforcement communications. The two most recent were issued in July and August respectively. Like the three before it, the letter issued in July was an Untitled (Notice of Violation/NOV) letter. However, the one issued in August was the first Warning Letter of the year.

The Untitled/NOV Letter. This letter was issued to CooperSurgical for a Direct-to-Consumer (DTC) television advertisement for an intrauterine contraceptive. FDA noted that the agency had received a complaint via the “Bad Ad Program” regarding the advertisement. Use of the contraceptive is associated with a number of contraindications listed in the PI, along with multiple warnings and a list of adverse reactions reported with the use of the product. It was the first letter for this manufacturer.

FDA expressed multiple issues associated with the DTC ad centered on the conveyance and balance between benefit and risk information and the concerns reflect past research performed by FDA regarding perceptions of such information in DTC formats. FDA claimed that while the ad had text that was superimposed with some risk information, it did not disclose all of the risk information from the PI. And in a voice over, the language stated that “If you experience pelvic pain…” rather than communicating that the product is associated with an increased risk of pelvic inflammatory disease.

What is perhaps most interesting was that FDA found that the presentation of risk information – by superimposed text and audio – was undermined by the simultaneous presentation of distracting visuals, scene changes and media which were unrelated to the actual risk information being discussed in the superimposed text. This, FDA said, would complicate the ability of the viewer to discern and understand the risk information. In 2016 FDA completed a study “Eye Tracking Study of Direct-to-Consumer Prescription Drug Advertising Viewing” where one of the findings was that distracting elements during presentation of risk information could impact retention of risk information.

Moreover, FDA said the ad communicated risk information in the visual portion of the ad only, but did not include major side effects and contraindications in the audio. In some cases, unrelated risk information was being portrayed simultaneous to audio information. Finally, FDA took issue that the ad repeatedly stated that the product was free of hormones which, while true, the agency felt that the repeated and emphatic repetition of this fact minimized the risks the product does have in its use.

The Warning Letter. This was issued in August, the first of the year. This letter went to Metuchen Pharmaceuticals for a DTC Print Ad and Display Banners promoting a product treating erectile dysfunction. It was the first letter for this manufacturer. The violations FDA cited were the Lack of Adequate Directions for Use, Misleading Risk Presentation and Misleading Claims on Efficacy. Given the breadth and scope that FDA went into with this Warning Letter, only the highlights will be covered here.

First the risk issues – FDA stated that some of the banner communications conveyed benefit without any risk information about the product. At times, some side effects were included, but not the contraindications or warnings. Likewise the print ad was cited for not stating any contraindications. In short, this stands for the proposition that risk information has to be complete in any conveyance, and presentation of some of the information does not cut it for OPDP.

Next, FDA also cited language used that the product was being termed as “next generation” and that this characterization lent the impression that the product might be safer and more effective than existing treatments.

The agency also took issue with what it deemed was an efficacy claim centered on language that promoted the product as something you could use “whenever you want”. FDA stated that the efficacy of the product was not shown beyond two hours and that dosing was recommended no more than once per day. Therefore the “whenever you want” use implied a window of efficacy beyond the 2 hour time period on the recommended dosing.

Most interesting perhaps was the claim made in the advertisement that using this particular drug allowed for the treatment of erectile dysfunction while at the same time reducing risk of heart failure. The agency said that this suggested that the product was safe for all patients at risk for heart failure and that while there is evidence that the class of product was she for some types of heart disease and people with some types of heart disease were not included in clinical safety and efficacy studies. It is a lesson on how easy it might be for a claim of benefit to stray outside the strict boundaries of the label.

As noted in an earlier posting, along with guidance documents and prior warning and untitled letters, the research agenda executed by OPDP provides some insight and should inform best practices in the development of promotional materials. We are up to five letters this year. We’ll keep watch and report on any activity for the final quarter.

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FDA OPDP Research – A Foggy Window into Future Thinking on Digital Media

FDA’s Study of Promotional Language Where There is Space Limitation May Provide Further
Definition in Digital

When one thinks of FDA’s Office of Prescription Drug Promotion (OPDP) there is a likely tendency to think of the regulatory action letters – Warning Letters or Untitled Letters -issued by that office to pharmaceutical companies about their promotional communications.

But there is another activity in which OPDP is highly engaged – one which informs that process – research. Each year OPDP executes a research agenda and publishes the results of the studies that it undertakes. And prior to engaging in research, the agency posts in the Federal Register a notice about each effort, soliciting input and comment from stakeholders.

The aim of the research efforts is of course centered on some shedding evidence-based light on various aspects of promotional language, formats and practices in pharmaceutical marketing. The goal is to provide a body of research by which FDA can assess the impact of promotion on the perceptions among target audiences with particular respect to understanding benefits and risks associated with a medicine.

But despite the mass migration by the consumers of healthcare information into digital information – along with the fact that increasing numbers of viewers are streaming away from commercial television, FDA’s OPDP – very late to the grasping the impacts of digital on communications overall – has mainly kept its research focus on the examination of very traditional communications vehicles. This has most particularly focused on Direct-to-Consumer (DTC) advertising on television. For example, in the “Completed Research” section of the OPDP site, some of the most recent projects completed in 2018 include

  • Market Claims in DTC Prescription Drug Print Ads
  • Impact of Ad Exposure Frequency on Perception and Mental Processing of Risk and Benefit Information in DTC Prescription Drug Ads
  • Hearing, Aging, and DTC Television Ads
  • Content Analysis of Accelerated Approval Prescription Drug Direct-to-Consumer Websites

But there is an important exception to the largely DTC focus in the current line up. Of the one dozen projects listed in the Research in Progress category is one that stands out – Character Space Limited Online Prescription Drug Communications. This research is to examine fair balance presentation in the confined space of Twitter (without saying Twitter) and other space-confined venues. In 2017, FDA published results from some very limited research on the promotion of prescription drugs on mobile devices.

Digital and social media has been a particular challenge for OPDP for a long time and there has never been a complete response to the framework of questions posed by the agency in the initial public hearing that was called to inform guidance development in this important area. The issue of character space limitation is an important one, not only because of the ubiquitous use of platforms like Twitter. Rather, space limitation also applies to small screens – such as mobile phones (not being addressed in this research). In 2014, five years after the initial public meeting on regulating digital and social media, FDA did issue a guidance document “Internet/Social Media Platforms with Character Space Limitations – Presenting Risk and Benefit Information for Prescription Drugs and Medical Devices” that provided a construct for how companies might address risk information presentation when benefit claims are made. The new research will take a closer look. According to OPDP’s description, the research project “is designed to address the question of whether substantive risk information in the character-space-limited communications is effective in communicating risks when benefit claims are made, or whether a link to the risk information is sufficient.” 

OPDP states that they will manipulate various scenarios to assess ability to include sufficient risk information in the context of a link. This is one to watch closely. While branded twitter feeds are not all that common, and product benefit mentions rare if not non-existent in that setting, the findings from the research project should be informative of how the office intends to respond, not only on twitter, but perhaps even in the context of a site that has been optimized for mobile viewing. And given the lack of specificity on digital by the agency, we have take any tea leaves we can get.

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FDA Sends CBD Related Warning Letter

This week FDA sent a Warning Letter to a company engaged in marketing products containing cannabidiol (CBD) to consumers for a wide variety of uses in both humans and canines. In addition to the letter, the agency underscored their action with a press release. It is not the first letter sent to a manufacturer of CBD. But the letter comes in the wake of a statement issued late last year by then Commissioner Scott Gottlieb in which he outlined the agency’s perspective on the regulatory oversight of CBD. The statement followed the passage of the Agriculture Improvement Act by Congress which allowed for the removal of hemp from the Controlled Substances Act.

In his statement, Dr. Gottlieb noted that while Congress could make hemp legal to grow, FDA would still exercise regulatory authority over CBD products even if the CBD were derived from hemp and not cannabis. He stated that where products are believed to put people at risk, FDA will act. He specifically called out the number of therapeutic claims being made about non-FDA approved products that contain CBD. (CBD, it should be noted, is the basis for one FDA approved medication.) FDA noted that marketing products with therapeutic claims could steer patients away from products that have been evaluated for safety and efficacy, and noted further that it is unlawful to introduce food containing CBD into interstate commerce.

In the Warning Letter to the manufacturer, FDA created action from Dr. Gottlieb’s words. The agency took issue with several product claims associated with products from the manufacturer. There were many statements cited by the agency regarding the marketing of disease-specific therapeutic claims associated with CBD such as “CBD has also been shown to be effective in treating Parkinson’s disease” and “CBD was effective in killing human breast cancer cells.” Additional statements that were less direct were also mentioned by FDA – “CBD has been linked to the effective treatment of Alzheimer’s disease” and “CBD is being adopted more and more as a natural alternative to pharmaceutical-grade treatments for depression and anxiety.” In other words, direct statements or more softened versions that imply a therapeutic outcome were both problematic. Obviously FDA is wanting to make clear for other manufacturers where the line is drawn from a promotional viewpoint as there are sites out there making claims.

At the same time, FDA has also put into place its laborious process for assessing and acting upon an issue – a meeting to gather input, a docket to collect comments as the agency considers strategic development of regulatory oversight. It is a lengthy process.

But as FDA makes moves to bring clarity to the regulatory environment, the market moves on. One has to ask oneself about the ultimate and practical impact of FDA’s efforts. The marketing of CBD-containing products is widespread and clearly mainstream. Fields of industrial hemp are being planted all over because there is a viable market for the use of the product beyond the development of FDA approved medicines. And frankly, if one visits other manufacturers of CBD-related products one finds the marketing of CBD dosages in various forms of conveyance – gummies, oils, drops, vaping liquids. While FDA’s letter was sent to a company where therapeutic claims were being made, a visit to many manufacturer websites reveals a market where there is no mention a product claim at all. There is a good reason for that. Everyone already knows the claims – they don’t need manufacturers to tell them. And moreover, even if a consumer does need guidance, there are plenty of non-manufacturer sites that provide a good deal of information about potential uses for CBD. So from a communications perspective, FDA has drawn a line. From the perspective of the market, the horse has long left the barn.

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What They Said – FDA Press Releases First Half 2019 – B.G and A.G (Before Gottlieb/After Gottlieb)

One of the many things notable during the tenure of Dr. Scott Gottlieb as FDA Commissioner was the change in communications – a change marked not just by style but substance. In fact, in a March posting here, it was observed that he had set a new bar that shaded the agency with a more “activist” character – tackling big issues and communicating the agency’s outlook and progress on them – from teen vaping to opioids to drug pricing. He used communications to more thoroughly and more regularly to inform the general public, draw lines in sand to opponents, address concerns of critics and keep members of Congress in the loop. It was not just the tone and tenor of the communications that changed, it was the volume. In fact, the number of communications missives from the agency rose dramatically. In 2016, the number of FDA releases was 122; in 2017 it was 164 and in 2018 it was a whopping 289. The numbers alone speak for themselves.

He also used the platform of Commissioner to more personally communicate himself – in the persona of the Commissioner, rather than the agency. He did so by utilizing a heretofore little used mechanism called “Statement from the Commissioner” – a form of press release that had been rarely used prior to his tenure as Commissioner but used once, twice, thrice weekly once he assumed office and got in the groove. It put a personal stamp on agency actions and conveyed to audiences that he was on top of a number of issues. Commissioner Statements in 2016 numbered only 1, but in 2017 it was 37 and in 2018 was 127, or about 44 percent of all FDA communications.

Dr. Gottlieb left FDA in early April. How has that impacted FDA communications, if at all? Did the pace of Statements from the Commissioner slow down? Well, yes and no.

Comparing the first six months of 2016, 2017, 2018 and 2019, here is how the numbers roll. The number of press releases issued by FDA has been on the rise since 2016 and looking at the measure half way through the year (represented in blue) one can see that more releases (154) were issued in the first six months of the year than in any of the years since 2016.

And as noted in prior postings on this topic, the number of Commissioner Statements, which are termed here as “Special Statements” certainly differed once Dr. Gottlieb became the commissioner. In 2016 Dr. Califf, Dr. Gottlieb’s predecessor, issued one. In 2017 he issued another. The rest that year were issued by Dr. Gottlieb and in 2018 one can see that the numbers were prolific.

Which leads to one of the changes that has occurred since Dr. Gottlieb’s departure. Rather than have statements from the Commissioner’s Office, a number of Special Statements have been issued by Office Directors and other senior officials. In fact since Dr. Gottlieb’s departure, of the 65 Special Statements issued so far this year, several have been statements by senior officials, some of which were issued by Dr. Sharpless as Acting Director. In other words, the Special Statements have become more democratized, spreading laterally in the organization rather than being concentrated in the Office of the Commissioner. It is difficult to say what, if any, impact that has on the effectiveness of the communications or whether now they are less “special” and simply are statement – or how it may differ once there is no longer the word “Acting” preceding the word “Commissioner”. That said, FDA is still using them to draw attention to specific issues and the progress FDA is making on them, as the one issued yesterday from Acting Commissioner Sharpless – “Statement on the Agency’s Actions to Tackle theEpidemic of Youth Vaping and Court Ruling on the Application Submission for Certain Tobacco Products, Including e-Cigarettes“.

As to subject matter, here is a breakdown of this year so far:

  • 9 Alerts on issues of public health
  • 43 Approvals
  • 79 “General Statements” which includes Special Statements
  • 22 Legal Actions – seizures, warning letter announcements, etc
  • 4 Rule or Guidance related statements

Perhaps the most notable aspect of all of this is that the number of missives from FDA has increased. If the six-month mark doubles for the year end, FDA will have issued more press releases than ever by my count. The agency has had more to say and is saying it more often (though July got off to a slow start with a huge gap in word from FDA from July 3 until July 15). We will revisit at year end to see how 2019 shaped up and what impact an appointment of Commissioner in the non-Acting capacity might have.


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