New OPDP letter with the type of violations seen in previous letters

 The latest OPDP letter, an untitled letter, came out this week and, as usual, there are interesting aspects to it.   Here are links to the letter and the promotional material:

Link to untitled letter: https://www.fda.gov/media/144115/download 

 Link to promotional material: https://www.fda.gov/media/144114/download

Here are some of the highlights of this letter:

1. The letter, addressed to Azurity Pharmaceuticals which was previously known as CutisPharma and is the parent company of Silvergate Pharmaceuticals which was identified in this untitled letter as the NDA holder at the time of NDA approval.

2. The letter appeared to be prompted somewhat, at least, by advisory comments provided to Silvergate, presumably on launch materials.  Those comments were completely redacted in this untitled letter so it is hard to say what FDA's advisory opinion was, exactly.  However, the mention of the advisory comments appears to signal that what FDA originally told Silvergate was not currently being followed in promotion of the drug in question, XATMEP® (methotrexate) oral solution.  

3. This letter, which dealt with an e-mail sent out by the company to HCPs, has a number of violations, some of which have been mentioned previously by OPDP in letters to other companies. These include:

    a. Put the safety information at the bottom of the e-mail below the signature line.  OPDP said, as it has previously, that putting safety information below a signature line or other signal that the document has ended minimizes that safety information.  In the past they have cited companies for having safety information at the bottom of a long (multipage) e-mail without any pointer to it in the e-mail.  They have also cited companies forplacing safety information at the bottom of press releases that had signals (for example, several hastags in succession) above the safety information indicating that the press release content was finished.

    b.  Had the boxed warning as the only balancing safety information for the claims in this piece.   I have seen this with other companies in recent months, thinking the boxed warning was all the safety information they needed to make significant claims about their product.   It stands to reason that since boxed warning products require the boxed warning just to have a reminder-like ad (product name only, no claims or representations that could be interpreted as real or implied claims), that you would need more safety information that would be contextual to your claims if, in fact, you had claims in your promotional piece. 

    c. Not having the right safety information.  The is an important violation and one not always cited by OPDP.  Azurity made a claim about easy dose titration and OPDP said that this should have triggered inclusion of safety language from the PI saying the drug should be taken weekly and that taking the drug daily could lead to fatal toxicity.  This likely came up in the advisory comments, based on the sentence immediately after the redacted section.

d. expanding the indication by shortening it in a succinct claim.  They e-mail template said: "I wanted to let you know that Xatmep® (methotrexate) oral solution is available for your patients with Acute Lymphoblastic Leukemia." OPDP opined that this implied that Xatmep had no age limitation on its use and had no limitations on its use, including that the statement, as written, implied that Xatmep could be used by itself and, although the OPDP letter didn't say it,  possibly as a first-line treatment.  The actual indication says that Xatmep was approved for pediatric patients and as part of a multicomponent chemotherapy treatment regime.  OPDP said that presenting the exact indication at the bottom of the e-mail didn't offset the expansion of the PI above, once again stating, as it has in many instances previously, that a company cannot mitigate a false or misleading statement by having correct information somewhere else in a promotional piece, especially if the correct information is minimized in some way (e.g., in a footnote or placed far away from the misleading claim).  Most interesting was that the e-mail template, one sentence previously, said "...[I am] a representative for Azurity Pharmaceuticals specializing in pediatric medicine." Apparently OPDP did not consider that the statement that this representative was a pediatric medicine specialist was sufficient to mitigate that the claim did not specifically mention pediatric in its claim language.   OPDP has, over the years for varying reasons, clearly stated that expansion of indication can occur from truncating indication language to save space and has ruled in an advisory comment that I am aware of that even when that truncation did nothing to change the meaning of the indication, OPDP wanted the company to use exactly the indication language as it appeared in the approved indication.  That advisory opinion is consistent with their opinion in this letter.

No one really knows what Azurity could have done to mitigate risk to avoid this letter but here are some simple suggestions that I think might have helped (changes in strikeout and red) without changing the e-mail language substantially:

1. Use a pointer statement to point to the safety information and define the group the drug is indicated for.   An example of how this might have looked would be "I wanted to let you know that talk to you about Xatmep® (methotrexate) oral solution (see Important Safety Information, including Boxed Warning, for Xatmep at the end of this e-mail).  Xatmep is available for your pediatric patients with Acute Lymphoblastic Leukemia.  It is also the first and only FDA‐approved oral  solution that is available..."

2. Include in the Important Safety Information standard safety information and not just the boxed warning.   Normally this would involve inclusion of contraindications and important AND relevant warnings, precautions and use information, in addition to the boxed warning and indication. 

3. Be a little more careful with how claims, including the truncated indication, are made.  For example, the claim pointed out by the FDA could have said:

"Xatmep may benefit your pediatric patients

• 2.5mg/mL provides easy, once weekly dose titration as body surface area‐based dosing is  recommended." 

As is the case with many pieces cited in letters from OPDP, careful choice of wording, appropriate inclusion of safety information, appropriate use of pointers and understanding what OPDP has said in previous letters to other companies and in advisory comments about promotional materials previously for that drug to your company could have changed this outcome for Azurity.  Hopefully you all found this analysis helpful.

Fall brings two warnig letters from OPDP

As the calendar turned to fall OPDP issued two warning letters.   

One letter went to Nalpropion regarding their promotion of Contrave.  Several things stood out about this letter:

1. The letter referenced a previous untitled letter from OPDP to Orexigen, the previous NDA holder, regarding the inappropriate promotion of Contrave (2017).  A search revealed that Nalpropion purchased most of Orexigen's assets in June, 2018 and the current OPDP letter was issued just a little over two years later.   The take home message here is one that has played out previously in a number of OPDP letters when a drug on FDA's radar is sold by a company and the next company may not know of or consider the previous regulatory history of that drug:  If you buy the drug from another company you inherit all the regulatory history, including history with OPDP.  One thing I think ad/promo professionals should do in cases where their company acquires pharmaceuticals and/or medical devices is to explore the regulatory history like original labeling discussions, FDA reviewer communications, submissions of promotional materials for advisory comments and other FDA communications.  In one case I have heard of a company was promoting its drug appropriately and had generated a number of compliant, internally approved promotional materials.  When the drug was purchased the purchasing company created a promotional campaign using a number of the claims that were not allowed by the ad/promo review team at the first company.  The result was an OPDP letter not long after the new marketing campaign went live.   So it might also be a good idea if your company purchases a drug to review the approved promotional materials that were obtained with the drug.   If a claim you think was obvious is not present, there is probably a good reason for that.

2. The letter referenced the use of a sponsored weblink to promote Contrave.   As with previous OPDP letters on the same subject, this letter pointed to 2 issues: 

(a) Sponsored weblinks don't give you much, if any, room for safety information.  The letter reiterates that links to that information are NOT sufficient when the ad actually makes claims, as this one does.  There are mechanisms for including safety information if you can add fields to the meta data in your web search result to include safety information.  Do a Google search for "Enbrel" and if you scroll down the search results you can see an example of how to do this by increasing the number of sub-headings you populate in your search result meta data.   I don't know if Nalpropion was offered that opportunity when they purchased the sponsored weblink space but, if it was an option and they had taken that option, they might have avoided an OPDP letter if they had done this as a means to include safety information.

(b) Sponsored weblinks don't give you much text to work with and so it is very easy to overstate safety and/or efficacy by summarizing in order to meet character limitations.   Using only the space they used in their sponsored ad there is no way to fit in all the necessary information, including limitations to Contrave's indication to help with weight loss.  If Nalpropion had limited their ad to say "See how Contrave can help you with weight loss.  Click here (leading to product website)" instead of "Lose 2-4x more weight on average..." they might have avoided this letter as Contrave is approved for use in conjunction with diet and exercise.

Also, as FDA considered this a serious health risk (Warning letter) Nalpropion will have to do corrective advertising.   As this was a sponsored weblink and it may not be readily known who saw this ad, it could be quite challenging for Nalpropion to execute this corrective messaging.  Also, if you read text OPDP is requiring to be included, it would be difficult to imagine doing it all in a corrective sponsored weblink. 

Finally, it is important to note that OPDP said that this letter, in part, was written to Nalpropion because of the FDA's Bad Ad program, which encourages HCPs to report false or misleading drug promotion. 

The other letter was addressed to Nephron Pharmaceuticals for their e-mails regarding Budesonide.

The letter said that Nephron had issued e-mails talking about the use of Budesonide to treat Covid-19 symptoms.   The issue, of course, is that Budesonide is not indicated for this use.  

There are several points about this letter that I want to highlight:

1. I do not see any reference to these e-mails being submitted to OPDP as promotional labeling.

2. The e-mails were apparently sent by the CEO and at least one of the sales reps, making it appear like promoting Budesonide in this way was a corporate strategy, not just a sales rep doing this on their own.

3. The title of the OPDP letter included the language "(COVID Related)"

4. This was also a Bad Ad letter

5. This was also a Warning Letter requiring corrective action by the company.

This is the first OPDP letter I have run across that referred to COVID and I wonder if there was a reason for them to have added this to the title of their warning letter.  It is not hard to understand that this could be a sensitive area with FDA and that, potentially, they wanted to address this with companies that are thinking about promoting or actually promoting their drugs as treatments for COVID-19.  Similar letters went out during the anthrax mail situation where companies were purporting their medications to treat anthrax and FDA sent out a number of letters saying that these products were not approved for those uses.   I was wondering when the first OPDP letter would come out relative to a company promoting its drug as a cure or symptomatic treatment for COVID-19.   Now we have it.  When you add to the nature of the promotion that no safety information was included, it is interesting to consider  why a company would knowingly sent out communications like this.

One thought that crossed my mind was whether these communications were sent out thinking they were covered under the Caronia court case First Amendment rights.  The letter would seem to indicate that these claims did not result from any scientific publications but rather the support was from anecdotal reports, some of which were from YouTube videos.  It will be interesting to see if any future letters come out about promotion of drugs off-label to treat COVID-19 or if companies will see this letter and not promote their products in this way.

  

First Letter for 2020

OPDP has issued it's first letter for 2020, this one to Outlook Pharmaceuticals.

This letter incorporates two themes OPDP has addressed in the past: (1) having paid search ads with claims but no fair balance and (2) Having an ad for an ADHD drug without risk of suicide in teenagers.

In 2008 OPDP sent out letters to 4 manufacturers of drugs to treat ADHD.   These letters all had one similar theme: No or limited mention of suicidality risks of these medications, especially in teenagers and the elderly.

In 2009 OPDP sent out letters to 14 companies for having claims in their sponsored ads without any fair balance.   This set out a series of events that led to Google actually getting involved and working with industry to come up with standards for these sponsored pharmaceutical ads.   What wasn't addressed was that companies could partially defeat this objection by OPDP by just putting the same information in the html backbone of their website so that Google and other search engines would be more likely to pull that information up as the search result for that particular drug.  In fact, in the screenshots of the sponsored ads for some of those 14 drugs some of the same claims were present in these so-called "organic" (not sponsored) search results.

OPDP later cited another company for placing similarly structured weblinks within a product website for another drug, again without presenting any fair balance for those drugs.

The most recent letter to Outlook Pharmaceuticals has claims without any fair balance which, in turn, means that they failed to mention anything about the suicide risks of their drug.

It should be noted that in my research over the last several years I have encountered a number of companies, especially those with their first drugs, who use sponsored ad search results to give the indication or drug class of their drug.   In most cases these are just statements or summaries of their indication and DO NOT contain any claim language.   Even some of the larger companies who led the way in removing claim language in their sponsored ads are now, years later, putting those claims in their sponsored ads.

As OPDP has done many times in the past, if they want to refresh industry on a subject they find a relatively to very onerous example of something they have sent letters for in the past and send out another letter or two.

The bottom line here is that paying attention to what OPDP has said not to do, even if it is warning or untitled letters from over a decade ago, is something that can keep you out of trouble.   At the same time, following what larger pharmaceutical companies do and accepting that as industry standard and, therefore, a low-risk practice is a good way to get into trouble with OPDP.

Vanda Pharmaceuticals Letter

Corporate websites are always a concern for Regulatory ad/promo professionals.   This is especially true for small companies that don't have their first approved product yet or for companies with approved product(s) that don't currently have product websites.

So, where do companies put things about their products in development or their product portfolio if they don't have or don't want to spend the money on product-specific websites?  It's a good question.

In my opinion, corporate websites are designed for people interested in the company.   Those would include investors and maybe, depending on how you look at it, payors,  caregivers, HCPs or patients interested in researching a little more about a company in their research on treatments.   So you have to put enough information on your website to peek the interest of investors and to give the rest of world a glimpse into what your company stands for. The conundrum, of course, is where does general information about a company and its products cross the line into specific information about products and, then, to product promotion?

The recent Vanda Pharmaceuticals letter sent out by OPDP is a case in point.    In looking at the webpage cited it does have indication-like information about two products but not real claims.   Just information about what the products do and pointing to the product website if the reader wants safety information.

To me certain things stand out about this letter:

• It appears that the violation was based on information that appeared on Vanda’s corporate website. 
• As there is no mention of this website being submitted to OPDP under 2253, it is very possible that the company considered this was a corporate website and, therefore, non-promotional and so they didn't have to submit the content to OPDP.  
• The violations cited were totally based on the company giving a pretty straightforward statement of what the product is used for.  No real claims except the indication statement.
• Finally, it appears once again that OPDP is connecting a boxed warning product with the distinction of whether they send out an untitled or a warning letter.

The bottom line here is that OPDP does consider corporate websites as potentially promotional and does review these ad hoc, looking for drug promotion.  

In my opinion this letter was sort of old school in that I think it was sent out, in part, to remind companies to keep their corporate websites totally non-promotional.  Consider yourselves reminded!   

So how should companies avoid these types of situations?  

1.  Take a look at your corporate website content and consider whether someone could reasonably consider that it is promotional.  Not whether YOU think it is promotional but whether some reasonable person might consider it promotional.

2. If you have product listings on your website or in a printed catalog be sure to group them in such a way that it doesn't appear that the grouping creates a claim.   Ditto for any descriptions that go with those products.  I am not saying to go crazy with this but consider if the grouping creates an indication for that drug.

3. Be sure that there isn't information on your corporate website about your drug or medical device that could be considered promotional.   These could include language that has inferred promotion.  Examples would be detailed mechanism of action discussions, summaries of what a drug is approved or being investigated for, detailed disease state discussions (especially if they go into the impact of or complications that could result from leaving a disease untreated or information about how current treatments are not completely effective) or anything else that could easily set the stage for drug promotion.

Look, any company that promotes their drug by doing more than handing out PIs is taking some risk that they may be violating ad/promo regulations.   Three keys to help avoid getting an OPDP letter or have an DOJ investigation is to do things the right way, not make careless mistakes and, finally, consider that any violation is too small for OPDP to cite you for.  Good luck!

FDA Guidance on Medical Product Communications

In June, 2018, FDA distributed a guidance document in the form of a Q&A describing under what cases material consistent with the PI but not in the PI could be disseminated.  
This guidance clearly defines that information inconsistent with the approved PI cannot be disseminated in promotional material.   These include:

1. Unapproved indications – including use as a monotherapy (if approved in combination), use to treat a different stage or therapy of disease, use to treat patients not included in patient population studied for drug approval)
2. Expanded patient populations if PI has limitations to the patient population
3. Conditions of use/handling/storage that are outside of what is in the PI
4. Dosing (e.g., amount, route of administration, strength) different from what is in the PI

FDA also indicated additionally, if the information communicated increases the chance that someone will be harmed by use of the product or if the instructions for how to use the product in the PI were insufficient to use the product in the way described by the communication, then, in both cases, the communication could not be used.

At the heart of this guidance is the idea that promotion has to be truthful and not misleading, some of the parameters of which are described within this guidance.   The importance of this guidance is that it allows the pharmaceutical industry to speak to things that they have not allowed previously, most or all of which have been the subject of OPDP action letters in the past.

What the guidance seems to say is that a number of areas that previously were either “gray”, undefined or clearly forbidden are now possible IF all the considerations above for the communication are met.  These areas that now appeared to be allowable are:

• Comparative studies – Routinely OPDP has said previously that companies should not talk about these kinds of studies unless FDA has seen the data first.   In other words, you had to have that information in the clinical section of your PI. 
• Providing context around (and softening of) statements regarding adverse events.  In the past if you had nausea as your adverse event and in subsequent studies not in the NDA you found that prophalaxis with nausea-reducing drugs eliminated most of this nausea, you really couldn’t say that as, once again, FDA hadn’t reviewed the data in those studies.  This was already mentioned in a 2014 guidance.
• Onset of action – Previously, if your PI was silent to onset of action you couldn’t mention it in your promotional material unless it was a fact but was just not mentioned in your PI
• Long-term safety and efficacy – Previously, you couldn’t talk about long-term efficacy if that data wasn’t in your label and FDA had not seen that data in their review.   Now, if data exists, you may be able to market to it without that data being included in a supplement to your PI.
• Sub-group analysis – As part of what was referred to, in a negative way, as ‘data mining’ it used to be prohibited to promote to sub-groups if those sub-groups were not specifically tested for in the endpoints of clinical studies.  Now it appears that if the data is present you can promote to these sub-groups.
• Composite endpoints – Previously you couldn’t say anything about the individual endpoints that make up a composite endpoint.   Now you can, with proper qualification, give some information about the results of the individual endpoints within a composite endpoint.
• Product convenience and mechanism of action – If new information not in the PI is available then it can be promoted to.   Interestingly, for product convenience this extends to comparative studies with competitive products, as well.
• Tolerability with concommittant drugs – Again, this normally had to be spelled out in the PI as did all information about drug-drug interactions.  Now it appears that information generated after the drug was approved can be marketed to, even if it is never added to the PI.
Of course, in all these cases the statements have to be truthful and not misleading and, as such would have to be scientifically sound.  Depending on the type of claim, the guidance also says that the evidence necessary might be substantial evidence and might only have to be adequate evidence.  Thus, you probably couldn’t do a sub-group analysis on blacks if only two blacks were enrolled in your piviotal study.  However, if you did an entirely separate study on blacks and it represented substantial evidence, the way I read this guidance is that you could promote to that study.
As is always the case, any information used in promotional material has to be truthful and not misleading.   This is always a high bar to hurdle and companies should make sure they are on strong statistical and scientific ground before they make claims that are based on data not addressed in their approved PI.

Arog Pharmaceuticals Untitled Letter

In a letter dated 6/29, OPDP told Arog Pharmaceuticals that they had been promoting their unapproved drug Crenolanib.

The crux of this letter was that it was OPDP's opinion that Arog was making conclusionary statements about Crenolanib although it had not yet been approved.

This type of letter has been sent out many times over the years by OPDP to companies for pre-approval promotion of drugs.   Looking back over past letters the theme is generally the same:

• Companies fail to make it clear that the drug is investigational and not approved
• Companies make conclusionary statements about aspects of the drug where no conclusion can yet be reached because the drug is not approved
• Companies give or imply an indication for a drug that has not yet been approved.  Obviously this is problematic to OPDP as in many cases there are limitations to an indication once approved.
• Use of words like novel or unique or other words that imply superiority
• In a couple of old examples, indicating lack of adverse reactions with the drug

In the current letter OPDP also cited Arog for indicating that their drug was useable with some forms of full dose chemotherapy.

In many of the letters and supposed promo materials sent out to OPDP, the supposed violations come down simply to choice of phrase.  It is impossible to know from the letters whether the company cited has chosen their words purposely, have just quoted words directly from discussion sections of scientific publications or, more simply, just believed so much in their product and were so unaware of the ad/promo regulations and previous OPDP letters on the subject that they didn't realize that what they were saying or doing was pre-approval promotion.

As I said, it is usually all in the language used.  In many cases just the addition, removal or substitution of a few words changes a claim to a statement of current belief (based on scientific data) about an unapproved drug.  Let's look at the language that was cited and see what could have been said (additions in bold, removed text in cross out):

Booth Graphics

o Combination Therapy—Future of A New Hope for AML Treatment 

     o CRENOLANIB - currently in clinical trials  

            o Also being investigated to see if it is combinable with chemotherapy at full doses

o The Goal: Eradicating Activating Mutations  

     o The Hope: CRENOLANIB  

          o Pre-clinical study results suggest that it could be a potent inhibitor of  

                o FLT3   

                o PDGFRα   

                o PDGFRβ 

Webpage

o  Crenolanib - A next-gen  new type of tyrosine kinase inhibitor for use being investigated for use in the treatment of FLT3-mutated AML. 

o Pre-clinical data suggests that Crenolanib, a type I TKI, is could be a potent inhibitor for FLT3-ITD and secondary KD mutants

THERE ARE SEVERAL ATTRIBUTES THAT HAVE BEEN DESIGNED IN TO THIS MOLECULE TO HELP SET CRENOLANIB APART FROM OTHER THERAPEUTIC OPTIONS 

1. In clinical studies Crenolanib, whether delivered by itself or as part of a drug combination, has shown showed benefit in FLT3 mutant AML. 

2. There is some evidence that patients who progress after treatment with prior TKIs may still remain sensitive to crenolanib. 

3. Evidence suggests that Crenolanib has favorable pharmacokinetics and does not appear to accumulate with repeated dosing. 

4. Crenolanib is was designed to be a selective type I TKI that does not inhibit wild-type cKIT.

Now, I am not saying that this language would be acceptable to OPDP as the language I suggest is not exactly scientific exchange and I haven't even read the science to see how definitive the results are, let alone know if FDA would think those results were definitive.  However, the changes I suggest would at least address most of the concerns OPDP presented in this most recent letter.  If we are to take the language in this letter as a signal from OPDP as to what would be acceptable to say about a drug that has not yet been approved but for which substantial data was available, then the message appears clear to me: Make clear the drug isn't approved and don't represent statements about the drug as fact when the validity of those statements will be dependent on the outcome of the review of the drug application by FDA and the resultant language in the approved full prescribing information.

Pfizer Untitled Letter Regarding Estring

I realize I am a little late to the party on this one as the last few weeks have been busy.  But let's dive in:

Pfizer apparently put a testimonial video together that featured a physician and a patient, both of whom were paid spokespeople for the company.   Although I have not seen the video, the OPDP letter was pretty clear.   The physician and patient spoke on THEIR experience with Estring, basically saying that they saw instant relief with no side effects.  However, as OPDP points out, this does not constitute a fairly balanced presentation of the benefits of the drug AND that these statements by the doctor and patient are, indeed, product claims and so must be presented along with fair balance regarding the risks of using Estring.   The video apparently did not have any risk information and referred the viewer to go to a product promotional website or talk to their doctor to get more information about Estring.

So this is a relatively cut-and-dry violation which once again shows that patient or doctor testimonials are promotional labeling/advertising and need to only be used in the following situation:

(a) when they represent on-label, average performance of the drug
(b) when they are presented with fair balance and access to the PI

For videos on the internet these could be handled by having important risk information and URL of the PI embedded within the video or, on a youtube channel, in the space that surrounds the screen on the youtube channel page.  In addition, you want to have careful training of the spokespeople as to what they are NOT allowed to say.  This does not mean you would tell them what TO say.   However, being upfront with people before a video is shot is much easier than having to try to edit a video after the fact to remove questionable statements.

It seems to me that every once in a while OPDP picks a topic they want to reinforce with the pharmaceutical industry and selects a company with a violative approach to use as an example.  While that may not be true the effect is still present.   This letter reinforces what I always tell clients regarding testimonials and what I tell my clients about testimonials is based on the experience I have gained by looking at past OPDP letters and attending national meetings where these topics are discussed.