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.