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 It is the aim that a proposed rule and a draft guidance will provide two means of impacting the price of medicines through different avenues of importation.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.

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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 vacancies
  • Bone, Reproductive and Urologic Drugs Advisory Committee – 2 vacancies
  • Gastrointestinal Drugs Advisory Committee – 1 vacancy
  • Non-prescription Drugs Advisory Committee – 1 vacancy
  • Oncologic Drugs Advisory Committee – 1 vacancy
  • Pharmacy 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.

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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.

  1. 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.
  2. 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.”
  3. 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.”
  4. 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.

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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.

Photo by Goh Rhy Yan on Unsplash

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