Mark S. Senak's Blog, page 9

Remaining Aloof from Politics

Yesterday FDA issued a press release regarding the much-anticipated actions related to the importation of prescription drugs. It is the aim that a proposed rule and a draft guidance will provide two means of impacting the price of medicines through different avenues of importation. The outcome is not certain and there is a long process ahead in relation to achieving any progress through these means. In other words, the pudding which will be the proof is far from being served up and there is plenty to discuss related to the merits and eventual impact of these actions, whatever headlines may say.

That said, the unusual thing about the agency’s press release was the headline – “Trump Administration takes historic steps to lower U.S. prescription drug prices” – noteworthy on a few counts, but mostly so because it mentions the name of the administration.

I went to my database of FDA press releases and did a search on the names of past presidents. Not one came up. This would appear to the be first time that the agency has issued a press release in this manner. If so, it is an unfortunate precedent.

Is there any real harm? Not in an earth shattering way. But in a highly polarized political environment such as we are in (yesterday there was a vote of impeachment), for a federal agency to engage in any communication that appears to be politically motivated may impact perceptions of impartiality. There are some agencies where there might be particular need to stay away from any political scent in its communications. FDA is one of them.

Several years ago when Plan B was applying for over-the-counter status, the stakes were highly political. Conservatives generally opposed the application while progressives generally lauded it. As the regulatory agency in charge, FDA had to ensure that any decision it was making was not based on politics but on data and science. That is one of the gold standards that must be maintained and preserved to reinforce public confidence in the actions that they agency takes.

It is not the rule, but the exception for there to be political aspects of a regulatory deliberation by FDA either related to an approval or a policy. But it does happen from time to time. For that reason, the agency should strive at all times to maintain the appearance of being separated from the fray and potential bias that can be associated with being political. For that reason if no other, the press release issued by FDA was a mistake – one the agency should take pains not to repeat.

Share this:

AdComm Drop-off in 2019 – FDA Consults Fewer Experts in 2019

The system of FDA Advisory Committees is in place so that when FDA needs advice – either on policy development, reviewing an issue with an already approved medicine, or regarding new drug approvals – the agency has a lot of expertise to consult. There are 31 advisory committees on hand organized by subject matter jurisdiction and expertise and 18 of them are under the category of Human Drugs. The Committees are comprised of a range of experts – from clinicians to practitioners to experts in clinical trial design and statistics. There is room for a patient and a representative from industry. They are summoned by the agency when considering a new drug or supplemental new drug application and generally meet about two months before the date set by the Prescription Drug User Fee Act (PDUFA) – also popularly known as the “PDUFA date”. They are not employed for use in every single approval decision, but in circumstances where the agency wants their input, usually the discretion of the division leader over the particular therapeutic category.

The agency has been asking for less advice than usual from the Human Drugs Advisory Committees – scheduling just 23 meetings this year, 19 of which were related to the approval of a new medicine . Granted, the year is not over, but given the organizational needs of holding such a meeting, FDA usually schedules them a few months in advance. There are unlikely to be any new ones scheduled for 2019, particularly given the holiday season will soon be upon us.

One possible reason for the need to consult with experts less frequently could be the emergence and uptake of Breakthrough Therapy status. This designation involves a more frequent and high level of consultation between the agency and the sponsor of a new drug application. Begun in 2012, the number of drugs that have been approved having had Breakthrough Therapy status has increased from 3 drugs in 2013 to 38 applications in 2018. The enhanced interaction between the drug sponsor and the agency may address many of the issues for which the agency would have otherwise sought consultation with experts.

Of course, another possibility is that there were fewer drugs to review. The number of NMEs approved so far this year is certainly less than it was last year. In 2016, there were only 22 NMEs approved, and 22 advisory committee meetings held that examined new drug applications. However in 2018 there were many more NMEs approved, but not many more advisory committee meetings considering NDAs for approval. This year, the number of NMEs has fallen, and so have the AdComms.

Whatever the cause, the notion that there are fewer AdComms may make lead some to feel there is less transparency to the process of approval. While they are long, and sometimes quite arduous to sit through, they are a setting in which one gets to see deliberation in action with respect to the approval process. You may not agree with everything, but you get to see it and hear it. Moreover, there is an opportunity for public input. There is a patient representative on each panel, as well as a non-voting industry representative. And perhaps most importantly in that regard, there is the Open Public Comment period during which patients, investigators and other interested stakeholders can share their outlook, experience and opinion and a docket is opened to receive comments. And it all happens before the media, who report on it in articles and on social media. Finally, if you miss it, there is both a transcript and a webcast. They are a complete learning experience for the observer, from providing insights into how FDA reviews safety and efficacy – how it develops concerns – what constitutes strength in clinical review and what spells weakness. We’ll have to see how next year shapes up.

And speaking of advisory committees, according to FDA’s current roster listings, there are currently vacancies on some of them.

Arthritis Drugs Advisory Committee – 2 vacanciesBone, Reproductive and Urologic Drugs Advisory Committee – 2 vacanciesGastrointestinal Drugs Advisory Committee – 1 vacancyNon-prescription Drugs Advisory Committee – 1 vacancyOncologic Drugs Advisory Committee – 1 vacancyPharmacy Compounding Drugs Advisory Committee – 3 vacancies

Finally, at year-end, I’ll provide a look-back on how AdComms fared with respect to new medicines.

Share this:

CBD and FDA – Where Are We?

Last week FDA and FTC jointly issued a warning letter to a seller of CBD products in Florida – the seventh such warning letter of the year. The letter took issue with the manufactuer’s marketing practices related to multiple products containing cannabidiol (CBD). Specifically, the warning letter was concerned with promotional language in addressing specific medical conditions, including teething and ear ache pain in infants, autism, ADHD, Parkinson’s and Alzheimer’s.

At the same time, depending on where you live, you may find you can walk into general stores, bodegas, cafes, fancy dog food stores and many other commercial venues to discover CBD in multiple products. This includes creams, gummies, candies, dog treats and in a huge assortment of teas (both ready-made and bags), to name a few. The stance taken by regulatory agencies against marketing of CBD products juxtaposed with our real-world, every-day experience of seeing CBD products for sale quite likely (and logically) leads to confusion about what exactly the status of CBD is. In addition, there was the high profile “Farm Bill” that got everyone’s attention that was supposed to change things – didn’t it? Where are we and where aren’t we when it comes to CBD?

Fortunately, there were extremely cogent and organized remarks delivered by the Principal Associate Commissioner for Policy from FDA’s Office of Policy at the National Industrial Hemp Council 2019 Hemp Business Summit held in August. They were extremely illuminating and lay things out pretty clearly. Here is a my take of what he said and here are the remarks to read for yourself if you like.

The Farm Bill (the Agriculture Improvement Act of 2018) made growing hemp legal. But marketing is a different issue. All cannabis products were Schedule I under the Drug Enforcement Agency system of classifying controlled substances – the most restrictive category. The Farm Bill removed hemp as an illegal controlled substance for federal purposes (when containing extremely low levels of THC – less than .3 percent). But it is FDA’s position as laid out by then FDA Commissioner Gottlieb in a statement on the issue, that the Farm Bill preserves FDA’s role in overseeing products containing CBD, whether from hemp or marijuana. CBD is in a prescription medicine. CBD is the active ingredient in an FDA-approved medication for epilepsy. FDA does not sanction the sale of prescription medicines as an ingredient in consumer goods. Of particular concern to FDA is the fact that while CBD has a benefit for the indication for which it has been approved in a medicine, the agency believes there is an uninformed long-term safety profile for its use outside of that medicine. Moreover, any claim associated with the use would be perceived by the agency as marketing a product that contains a medicine for uses other than for which it has been approved. As stated in the remarks “…if a product is marketed with a claim that it will diagnose, cure, mitigate, treat, or prevent a disease, then it generally will meet the definition of a drug, and it will be subject to FDA’s drug authorities.”What if a product containing CBD does not make a claim? If the product is an area still regulated by FDA, it may be subject to agency authorities – this includes pet medications, cosmetics, foods and dietary supplements. And all of these are regulated differently. In particular, food additives must be determined by FDA to be safe. There are exceptions, but they are limited and FDA does not regard CBD as fitting into the reasoning behind the exceptions. And when it comes to supplements, any supplement that contains a substance that is approved as a drug, is not by definition a supplement. “This means that under current law, it’s unlawful to sell a food or dietary supplement with CBD in interstate commerce.”So where does that leave us? Exceptions can be made by the agency. But FDA is a data-driven agency and any exceptions would likely have to have a foundation of data. Questions need resolution. “For example, how much CBD is safe to consume in a day?” What if someone ingests CBD from several sources/products at once? There are a host of questions the agency has with respect to exposure – related to both benefits and risks. The agency has put into place an internal policy working group to examine and evaluate CBD-related questions and the matter of CBD was included in a public hearing on cannabis the agency held in May. The docket receiving public comment has gotten nearly 4,500 comments which the agency is assessing. The agency may decide it needs additional authorities from Congress, which will certainly take time. They are looking for additional data.

In the meantime, the market moves on. The CBD horse has not only left the barn, it has crossed county and state lines and is galloping far and wide. While FDA seeks more data upon which to make decisions, the market itself is providing the laboratory, and consumers are making their own decisions. People all over are consuming a wide-range of CBD-related products in all sorts of quantities with variable quality and for a multitude of reasons. The answers to FDA’s questions are out there certainly. To help with keeping tabs on CBD, FDA has created a page that embodies all things FDA and CBD and it can be found here.

Share this:

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.

Share this:

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.

Photo by Goh Rhy Yan on Unsplash

Share this:

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 AdsImpact of Ad Exposure Frequency on Perception and Mental Processing of Risk and Benefit Information in DTC Prescription Drug AdsHearing, Aging, and DTC Television AdsContent 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.

Photo by William Iven on Unsplash

Share this:

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.

Photo by Rick Proctor on Unsplash

Share this:

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 health43 Approvals79 “General Statements” which includes Special Statements22 Legal Actions – seizures, warning letter announcements, etc4 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.

Photo by AbsolutVision on Unsplash

Share this:

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.

Photo by freestocks.org on Unsplash

[image error]


Share this:

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.

Photo by Goh Rhy Yan on Unsplash

Share this: