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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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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