OPDP Finds another Kardashian sister in their 3rd letter this year

 OPDP sent out their first untitled letter (3rd letter overall), in a letter dated Monday, March 8th.   

This letter, sent to Biohaven Pharmaceuticals about their migraine medication Nurtec ODT, involved a testimonial interview with Khloe Kardashian.   Not lost in the irony of this letter is that in 2015 Kim Kardashian was the testimonial-maker in her tweet about how effective Diclegis (Duchesnay Pharmaceuticals) was at treating her morning sickness.  

These two testimonials had a lot in common

• The testimonial-giver presented their own experience which was way above average for what would be expected with the drug they were prescribed. (overstatement of efficacy)
• There were inferred comparative claims
• Both letters were due, in part, to a complaint to FDA's Bad Ad Program.

The most recent letter also had some other elements in it not in the previous letter:

• This testimonial was a video (not a tweet like in the first letter)
• This video was designed to be promotional as it had ISI at the end
• This video was not submitted to OPDP at time of first use.

The main things from a Regulatory standpoint, that were important about this letter were:

• The testimonial contained numerous overstatements of efficacy (e.g., time of onset of action) and comparative claims (e.g., nothing else had worked or only worked for a short while)
• Single words like "gamechanger" represent significant superiority claims
• The ISI was at the end of the interview in small letters which were on the screen for 4 seconds and was preceded by a statement by the moderator ("we'll be right back") that would infer the end of the interview.  So , instead of a callout (signal) that the ISI was coming, the ISI was minimized, similarly to when a press release puts ### above the ISI.
• Failure to submit a clearly promotional piece at time of first use. 

The first two bullets are typical of many OPDP letters in the past and point out the problems with using testimonials.   The spokesperson is not just giving their opinion.   Their words actually become promotional when linked to the manufacturer of drug or even, in some circumstances, with the disease state if that testimonial is tied, in some way, to the product class.  Normally what I have found is that a good testimonial agreement is a good place to start with someone giving the testimonial.   This agreement should note that the product exists in a highly-regulated industry and that company has the right to modify or not use the testimonial if they feel it is overly and unduly promotional.  People who give testimonials rarely understand the guard rails that companies must operate in so inclusion of language in the agreement about what is appropriate and what is not appropriate is always helpful.  

The 3rd bullet talks about minimizing the ISI.  Use of "supers" to point to the ISI at the end and to point out the limitations of use in the product are very helpful in balancing the claims.   Also, if care is taken to avoid statements like "we'll be right back" and other signs that the video content has ended that would help.   

The final bullet, failure to submit under cover of Form 2253, is interesting.   Research I have done shows that when FDA says this they don't always mean that the piece was NEVER submitted.   It also can mean the piece was submitted late compared to when it was first used.   The examples I found had pieces that were submitted to OPDP anywhere from 30 days after they were first used up to 5 years after they were first used.    In this case, as with other cases like this, it is impossible to tell how long it was after first use the piece was submitted to OPDP, if at all.

As a final note, normally videos like this are pulled by companies soon after the OPDP letter goes out. A quick search of YouTube and social media found the following videos that were still up today (March 11th) that contained claims from Kardasian on Nurtec.  Not all of them were company-generated but, normally, this is all cleaned up immediately after OPDP issues a letter like this.   Interestingly, not the case in this situation.

Khloé Kardashian Has Suffered from Migraines Her Whole Life - YouTube

If you google you can also find promotional Twitter and Facebook postings/videos that contain some of the same claims (e.g., 15-30 minute relief) that were mentioned in the OPDP letter.   At least at this point, Biohaven has not removed this information from the internet.   Time will tell to see if it is/can be removed.   

 

Second OPDP Letter of 2021 - Previous Communication Leads to Heightened Surveillance

It didn't take OPDP long to issue its 2nd letter of the year.   This time it was a warning letter to Cooper Surgical for its promotion of PARAGARD” (intrauterine copper contraceptive).  

This letter had familiar aspects to it seen in previous letters from OPDP:

• Resulted from a complaint through FDA's Bad Ad program
• Followed another letter to Cooper Surgical about the same product in 2019
• Concerned a video that mentioned the company and product name and had both inferred and real claims about PARAGUARD but did not have any safety information.
• Video was not submitted under cover of Form 2253 at time of first use
• As a warning letter it required Cooper Surgical to do corrective action

The letter also had some interesting aspects to it:

• The first footnote of the OPDP letter implied that OPDP first saw this video on October 5, 2020 and last accessed it on February 12, 2021, the same date as the letter sent to Cooper Surgical.
• The letter invited Cooper Surgical to contact OPDP if it wanted to discuss OPDP's concerns and to provide evidence that the video was not violative

SUMMARY

On the surface, this letter represents to just represent low-hanging fruit for OPDP. It points out that receiving an OPDP letter places the company, in general, and the product that was the subject of that letter, specifically, under heightened scrutiny for future promotion.   But there is more to this letter than that.

Looking a little deeper it also interesting that both the 2019 and 2021 letters to Cooper for PARAGUARD resulted, at least in part, from complaints through the Bad Ad program which could imply that HCPs are looking at a company's ads more closely after an OPDP letter is issued.   

Also, the description of the violations in the most recent letter to Cooper (no ISI, no submission to OPDP) could imply that Cooper either did not know about this video or that they thought that it was educational and non-promotional.   There have been other examples in the past where a company did not know that a TV commercial had been produced and that the agency that produced it might not have understood FDA regulations on fair balance, etc. required in a drug promotional ad (e.g. Rozerem TV ad).  There are also examples where companies have included reference to a drug in an otherwise educational piece which, of course, rendered the entire educational piece promotional e.g., (Ovide letter).  

It is not clear so I cannot speculate on these possibilities but it is hard to believe that a company could have received an OPDP letter on a TV ad for PARAGUARD and, about a year later, knowingly produced/approved another TV spot that was so obviously violative, as well.   My guess is that there has to be more to the story than what is evident from the letter.

It is also intriguing that this video was viewed by OPDP four months before the Warning Letter was sent out.   Historically it has taken longer for Warning Letters to be issued as they required extra review within FDA before they are sent out.   The interesting part is that the violation was discovered under one political administration, but not acted upon until the next political administration took over.   As I said in my last post this is a trend that will have to be watched in the future as it is my impression that the previous administration believed that FDA was, and should not be, putting up too many roadblocks to the pharmaceutical industry.   Although the number of OPDP letters issued in a given year can vary dramatically from other years and, whenever this happens there has been a lot of speculation regarding trends like this, it is generally not known if there is, in fact, any real reason for this or if it is just yearly variation.  As I said, it will be interesting to watch in the future to see if the trend in an uptick in OPDP letters continues in 2021 and into 2022.  

Finally, although it might not mean anything, it is interesting that OPDP invited Cooper not once but twice in the conclusion to the recent letter to contact OPDP if they wanted to discuss this.  Invitations like this are generally part of the boilerplate language in some OPDP letters but this time that language just struck me as being slightly different in tone than previous times I have seen it.

Hopefully this analysis was helpful to you.

First OPDP Letter of 2021

OPDP did not waste much time in inputting their first letter of 2021, a warning letter to AcelRx Pharmaceuticals for ads regarding their sub-lingual opioid medication, DSUVIA (sufentanil) tablets.

Interestingly, OPDP has included a new document with this first letter.  The document, called the "CDER Statement" outlines OPDP's concerns with the promotional material they are citing.  In addition to summarizing the CDER/OPDP opinion that led to the warning letter, the CDER Statement also, once again, solicited HCPs to report inappropriate promotional activities and everyone to report adverse reactions, medication errors and the like.

The OPD letter concerned two promotional materials but with the same claim "Tongue and Done".   FDA took offense to this claim being in big letters in a tabletop display and on a banner in a pormotional booth, both of which were presented at a conference.

Here is the breakdown:

THE BAD

• They objected to the tag line, itself, as oversimplifying the use of the product which has serious limitations to its use which were outlined in a REMS.  The letter stated that as DSUVIA is an opioid its use and disposal, consisting of 7 steps, is not simple as is implied by the simple tag line.  
• OPDP was also concerned that the PI for the product said not to use more than 12 doses per 24 hours.  The banner included the statement "Minimum dosing interval: 1 hour" but did not include the material fact regarding the maximum number of doses per day, giving the impression that you could take as many as 24 doses in a day.
• Both promotional pieces made claims and representations in large letters that needed fair balance but that fair balance was only present in small font in paragraphed ISI. 

  THE INTEREStiNG

• OPDP did not object to the table top graphic having pointer to information (indication, ISI, limitations of use and boxed warning being available in the convention booth (as opposed to being available from a sales rep in the booth).  Interestingly, this pointer could have meant that the ISI was on a different placard somewhere in the booth.  It is a little confusing as the ISI appeared to actually be on the table top graphic
• OPDP did not comment on why there was no appropriate pointer to the PI.   In fact the ISI on the tabletop graphic did have what I would refer to as a "non-pointer statement" which said "Please see Full Prescribing Information and Directions for Use."  Pointer statements are supposed to point to something but OPDP did not object to this pointer statement not pointing to where the PI was available.  As said above, OPDP likes the PI to be available in the booth without the reader having to go to a sales rep to get the PI.
• OPDP did not object to the second tagline that said "Effective Pain Relief   Efficiently Delivered."  This statement was right above the ISI on the same page.
• These materials were dated 2019, meaning OPDP may have taken 2 years to act on them.   It is not clear whether this was due to the pandemic or whether it might have been due to a change in political/governmental administration.  In any case, it will be interesting to watch whether this the beginning of a trend that sees more letters in 2021 than in previous years due to either or both of these factors.    

SUMMARY OF LETTER AND PROMOTIONAL MATERIAL

FDA (and DOJ) have shown in the past that they are very serious about taking steps to lessen the opioid epidemic.  For OPDP, this means being very precise with language and following the regulations on fair balance and inclusion of material facts, especially in light of these products having REMS that they need to follow which emphasizes, among other things, training on appropriate usage and disposal of opioid-containing pain medications.   

So, for OPDP, this was low-hanging fruit.  But what does it teach those in the rest of pharmaceutical industry about their promotional materials?

This letter points out the risk of leaving out or minimizing fair balance, material facts and other, more general, important safety information.   It is possible that directly including the limitations of use right below the tag line "Tongue and Done" and the claims "Minimum dosing interval: 1 hour", "DSUVIA comes in one strength for acute pain" would have mitigated the risk sufficiently for OPDP.  As said above, OPDP did not comment on the side of the tabletop graphic when the other tag line "Effective Pain Relief  Efficiently Delivered" was used with the ISI right below it, even though the ISI was in small font in paragraph form (i.e., not bulleted).  

I am sure that many of us have seen ISI similar to what is on the tabletop graphic and the banner ad and the ads that use this presentation have not received an OPDP letter.  We have probably also seen tag lines like the ones in this piece, likely where the ISI was separated from the tagline and in small letters, with the ISI maybe even being in paragraph form like this one.   We have likely all seen these tag lines being devoid of mitigating statements with the tag line, with all the mitigation relegated to a block of ISI, minimized by being in small font in paragraphed form.  And none of those pieces ever received an OPDP letter!!!!! 

That is really, for me, the takeaway point of this first OPDP letter of 2021.  Just because you don't get a letter for having tag lines that don't include fair balance or you relegate your ISI to paragraphed form in small font way separated from your claims, doesn't mean it isn't a violation.   My opinion is that it is probably the WORST type of violation for a pharmaceutical company to make in its promotional materials because it could easily be avoided.   So, my request to all of you is to be aware of how tag lines could be misinterpreted.  Where material facts need to be included, give appropriate weight to those facts in conjunction with the claims/tag lines you are using.  Finally, put ISI in bulleted form with white space between the bullets, use some ISI on every page if you can do it and don't minimize the ISI in any way: size, contrast, ordering of ISI or other factors.

To conclude, the first OPDP letter of 2021 could easily be written off to OPDP coming down on an opioid manufacturer with a REMS on their product in the middle of an opioid epidemic, but most of us shouldn't take it that way.  In my opinion, this letter should be seen as a gentle reminder for the rest of us to take more care in balancing the benefit and risk information in our promotional pieces.   That is a message that OPDP has delivered to industry for decades now.   This is just a little reminder to all of us not to forget these important considerations when we are reviewing promotional materials.  

Does Your Ad/Promo Team Need a Refresher Training?

 There are lots of people who are involved in the creation and approval of pharmaceutical and medical device promotion.   Regulatory, Medical, Legal, Marketing, Market Access and Training, to name a few, would benefit from having occasional refresher trainings on ad/promo.  Even executives would benefit from a short refresher/training course on advertising and promotion basics and common pitfalls.

I have found that even if companies offer basic training for their employees, refresher training on advertising and promotion is something that generally falls through the cracks. 

Nosco Consulting offers two courses:

1) Basic/refresher course:  This is a 3 hour training that is done remotely.   It covers the basics of pharmaceutical and medical device promotion and gives plenty of hypotheticals and real life examples that help people navigate through how to create compliant and effective promotional materials.   Even if your team or individuals on the team have had Ad/promo 101 training in the past, this course will likely offer a different, entertaining approach to this subject that will help stimulate thought and create a better process at your company.  

2) Executive course:  This will be a 1 hour remote  course that will focus on current thoughts on promoting pharmaceuticals and medical devices in the current environment.  It is designed to be thought-provoking in regard how the regulatory landscape is changing in medical product promotion and to help align the executives with the promotional review process that is going on in their company.   The course looks at the world through the eyes of pharmaceutical promotion but also should be useful to executives at medical device companies.

If you are interested please feel free to contact me at dnosco@hotmail.com 

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.

Collegium Pharmacauticals Letter

OPDP issued its first (untitled) letter of 2018, 3 months ahead of the pace in 2017 when the first letter came out in May.  The letter was sent to Collegium about their promotion of the extended release opioid product, Xtampza ER.

To summarize, the letter claimed that Collegium did not provide Important Safety Information WITH the claims in a booth panel or in a similar prominence, failed to provide appropriate materials facts (regarding abuse deterrence) and put some material facts in a position on the booth panel that were close to floor level and obscured by a table and chairs.  The backdrop of this letter is that Xtampza ER is an opioid product and in light of the opioid epidemic in the country, serious risks of opioids need to be appropriately pointed out when opioid products are promoted.

There is some sentiment in the industry that a promotional booth at a conference is one large promotional piece and that each booth panel does not have to have fair balance if the booth, as a whole, is balanced.  This letter seems to indicate that OPDP doesn't see it that way and that Collegium exacerbated the situation by having the fair balance in different prominence than the claims.   OPDP also took particular exception to placing material facts near the floor of the exhibit panel, obscured by a table and chairs.  Both the disconnect of the Important Safety Information from the claims and the obscuring of the material facts were probably considered by OPDP to be basic mistakes in promotion of a pharmaceutical.  Reading between the lines of the letter it appears that OPDP is saying that these types of basic mistakes are even more objectionable when a company is promoting an opioid.

At this point I will interject my own opinion.  Every company has key points they want to make in their promotional materials.  These are points that in many cases differentiate their product from the competition.  Some of those points may be in the gray area of what is allowed based on their product package insert.   I think this letter points out that if you want to make those claims you should make sure that the rest of the promotional material is pristine in terms of things that could be construed as violations of the promotional regulations.  This letter seems to say to me that OPDP thought Collegium was trying to get every little edge in their promotional claims, in some cases going so far as to do things that appeared to be silly, like putting material facts so low on the booth graphic they almost became footnotes.  I think OPDP looks at promotional pieces as a whole. If that is true, trying to gain every little possible edge can create a straw-that-broke-the-camel's back situation compared to just making one or two appropriately balanced claims that fall in that gray area with the rest of the piece being on point relative to the regulations. I could easily be wrong but this is how I feel I have been successful in my career at helping companies create compliant promotional materials that are, at the same time, effective.

In addition to the above, the origin of the letter and the context of OPDP citing previous communications with Collegium are interesting.  

1. The letter indicated that the violations were observed by an OPDP representative at a meeting in June, 2017.  This shows that even in the new political administration where OPDP regulation may not be as important, OPDP is still going to meetings and looking for promotional violations. Additionally, the lag between when the violation occurred and when the letter issued fits with what I have seen for previous OPDP letters over the years, on average.

2. The letter referenced advisory comments that OPDP had provided to Collegium regarding other promotional materials for Xtampza ER.  In those advisory comments OPDP asked Collegium
to modify those materials to correct many of the same issues that OPDP found with the booth panels. This is not the first time OPDP has referenced previous communications in an action letter but it again points out that refusing to heed OPDP advice can increase the risk of an OPDP letter regarding future promotional materials that have the same issues.  Bottom line: if you choose to or are compelled to seek advisory comments from OPDP, it is wise to heed those recommendations.   Failure to do so can just add more straws to that already weakened camel's back.

None of what I have said above is intended to condemn Collegium's internal review process, what they intended to do or what is done at OPDP.  It is just my opinion on how this letter can be an example that can help companies do a better job of creating compliant and effective promotional materials.

UCLA OPDP Letter

In its latest action letter, which came in under the wire for 2017 as it was issued on Dec. 28th, OPDP cited the University of California at Los Angeles (UCLA) for its promotional claims about an unapproved drug, a radioactive imaging agent, Ga68-PMSA, used in positron emission tomography (PET).   Promotion of unapproved drugs as a specific cause for an OPDP action are relatively rare and a quick search by me could come up with less than 30 letters since 2000, with the vast majority of those to pharmaceutical companies.   In fact, this letter represents only the 2nd letter I could find in that period sent directly to a university for promoting an unapproved drug.  The other letter went to UCLA, as well, a couple of years ago (2015).

OPDP cited UCLA in its 2017 letter for a number of promotional claims about Ga68-PMSA, saying that those claims fall outside of what is allowed for discussing unapproved drugs, i.e., dissemination of scientific information.   Looking at the claims and materials OPDP cited, it appears that OPDP is correct.

As background, there are many recent literature reports about the promise of Ga-68 radiopharmaceuticals for medical imaging.   The results of scientific studies for Ga-68 PMSA are very promising.  However, it is the use and, more accurately, the summation of the results of that scientific data to promote a patient to ask to have this scan or HCP to suggest this scan that is no doubt concerning to OPDP, considering that there is no FDA approved version of this drug.

I think the fact that this came from a university-related medical center is interesting and the fact that it follows on the 2015 letter to UCLA for promoting [F-18] FDDNP, another unapproved PET imaging agent is also of note.

So, what is to be learned from this letter?

What I am about to say is my opinion and, in no way, is meant to say that UCLA did anything malicious.   However, in my experience, scientists not trained in the rules of promoting pharmaceuticals usually don't understand the difference between just giving information to people and active promotion of an unapproved drug.  As I was a drug discovery scientist at a pharmaceutical company before moving to Regulatory Affairs, I get it.  What scientists may consider a fact based on available data is, to OPDP, an unsubstantiated claim if the drug under discussion is not FDA approved.  Scientists don't normally understand that even though a drug may look good in a limited study, it could have risk-benefit limitations that might make it not approvable by FDA or that there may need to be some significant restrictions in use if the drug is approved.   They don't understand that those determinations can only be made after looking at larger studies and all the associated data (e.g., manufacturing) that goes into making sure a drug is safe and effective for human use.  This is not meant as a slam against scientists, it's just my experience as a former scientist and a regulatory person who deals with these scientists in a promotional setting.

This letter and the previous letter to UCLA point out the need for good Regulatory advertising and promotion training for universities and medical centers that are using unapproved drugs.  It also would be helpful if the content of outwardly-facing materials (e.g., websites and brochures) underwent review by someone experienced in OPDP regulations.    Finally, it should refresh for pharmaceutical companies the necessity to have good oversight with the universities that are conducting their clinical trials and the materials those institutions are using to recruit patients.  

Package Inserts in Promotional Materials

Over the years I have seen and heard of a lot of different options for use of package inserts (PI)  also called full prescribing information, in conjunction with promotional materials.

When the regulations call for promotional materials to be accompanied by adequate directions for use, for pharmaceuticals we are talking about the PI.

The question is, what do companies think "accompanied by" means?  There are really two general categories: electronic pieces and hard copy pieces.   Here are some thoughts about each:

ELECTRONIC PROMOTIONAL PIECES - Non-narrative

There are many kinds of electronic promotion: e-mails, websites, electronic ads, social media, internet videos and TV/radio ads.   In all but the last category, the PI is normally 'provided' by including a link to the PI.  That link normally goes to a pdf version of the PI on a product promotional website. If this method is used the link should probably go DIRECTLY to the pdf of the PI and not to the homepage of the website.   Other methods exist like creating a hidden website that only has the pdf of the PI and then linking to that single webpage website.  By standard practice, for TV/radio ads the viewer/listener is directed to a printed ad (or a website URL) that contains the PI.   OPDP has said that internet videos are more like websites than TV ads and, in fact, if a TV ad is placed on the internet (e.g., on YouTube) a company should provide a link to the PI page ON the internet page with the video instead of within the video telling people just to go to a magazine to find the PI as they do with TV ads.  In other words, OPDP feels that once a TV ad is on the internet where space or time is not limited, normal internet rules regarding the inclusion of the PI apply.

ELECTRONIC PROMOTION - Narrative

 During a product promotional presentation like a sales presentation on a tablet/laptop or a product promotional slide show, a hard copy of the PI should be handed out at the beginning of the presentation.   In these cases it would likely not be sufficient to simply show the PI on the presentation screen as that would likely not represent ADEQUATE directions for use.

NOTE: If you are presenting a webinar there are four options I have seen used:

• E-mail the PI to each webinar registrant with the e-mail confirming their registration 
• Shortly before the webinar is supposed to start e-mail the PI to all participants 
• In the confirmatory e-mail provide a link to the PI 
• For hard copy confirmations, include a link to the PI on a postcard with appropriate text letting the reader know what the link is to or for a letter confirmation, include a copy of the PI

Companies should decide which they feel is best for them logistically and for regulatory compliance.

PRINTED PROMOTIONAL PIECES

For printed materials, there are a number of different ways that companies provide PIs with their promotional materials:

1. They print the PI on the promotional material
2. They glue the PI to the promotional material using a sticky, glue-like substance that allows easy removal of the PI
3. They include the PI in a sleeve between two pages
4. They include the PI loose inside a multipage piece
5. They provide the PI separately (but at the same time) as they distribute each promotional piece

There are reasons that companies have for using each of the above.   Based on my experience here are those reasons as I understand them as well as the pros and cons of each one.

1. Some companies feel that it is better if the PI is part of the piece so they know the viewer will receive the PI IF they receive the promotional piece.  Also, for a magazine ad, the inclusion of the PI is a requirement (along with the major statement important information (including safety information) about the product.  In this case a company would have little choice but to buy a couple of extra magazine pages to print the PI.   As indicated above, this does help the company if they are running TV ads about the product as it gives them a place to point viewers to see a copy of the PI.

pros -You will never have a promotional piece given out without the PI; pieces tend to stack better than if you use the glue idea.

cons - If your PI undergoes a substantial safety labeling change that the FDA deems important enough to require the company to implement immediately, you could end up trashing a whole bunch of your promotional pieces (or, in the case of a TV ad, having to reshoot the ad).   Reprinting (or reshooting) these could eat up a good amount of a marketing budget, especially if it is a popular piece.

2. This seems to be very popular and provides a great way to get the PI (usually folded up to a small size) attached to the piece but easily removed from the piece if someone wants to read it.

pros - The PI is affixed pretty tightly to the piece so it is unlikely to be accidentally dislodged.  As above, this eliminates a lot of the human error in proactively giving out the PI.   In some cases, it also makes it possible to replace the PI with a newer version if necessary, although this is not always possible.

cons - Promotional pieces end up with a lump in them, making them harder to store and bulky to pass out.  It may not be easy to remove the glue and replace with another PI if a PI change is mandated so you could end up trashing your promotional material.

3. This requires a piece to have two pages permanently glued together at the sides and bottom creating the pocket.

pros - The best option if you want the PI to be non-obtrusively included AND easily swapped out if a PI has to be replaced.

cons - Probably the most expensive way to include a PI as, for a single page sell sheet, you now have to create a pocket which might more than double the cost of printing.

4. The lowest tech option which can involve the PI (flattened out to make it fit better between pages) being added after printing or can involve the person distributing the promotional piece to a customer or patient actually slipping the PI into the piece before they distribute it.

pros - least costly of the ones so far and represents the easiest option in terms of replacing the PI if replacement is necessary; some companies even provide a set of PIs in a stack like a notepad where a PI is just peeled off every time it is needed (thus, if the PI is changed, the pad of old PIs is just destroyed and replaced with a pad of the new PIs)

cons - this represents one of the greatest risks for the PI not being given out with the promotional piece so when this method is used, the PI is almost always provided with piece as it comes from the printer; most companies still don't feel comfortable with the possibility that some employee may forget to include the PI when they distribute a piece.

5. This separates the act of giving out the promotional piece from the regulatory requirement of providing the PI.   In additional some companies feel that all they have to do is OFFER the PI, whereas other companies feel they have to provide the PI.   For the former group, having PIs available but not included cuts down printing costs of having to include the PI, even loosely, with the promotional material.

pros - If a company feels that their employees are well trained enough, this option represents the most cost effective and versatile (in case of a PI change) way to satisfy the regulations

cons - This option provides the greatest opportunity for someone to forget to provide the PI with the promotional piece and probably requires the most oversight of these 5 methods to make sure a company is being compliant in providing the PI to the person getting the promotional piece.

FINAL THOUGHTS

As product promotion changes some of the above methods of promotion may become obsolete.  They key for me is to make sure that the person receiving the information has access to the PI that is commensurate with the nature of the presentation of the promotional materials allowing, of course, SOMEWHAT for limitations in the nature of the promotional materials.  Notice that I said 'somewhat' as OPDP has said repeatedly that limitations created by use of certain methods of promotion does not eliminate the requirements for fair balance and providing adequate directions for use.   As companies move into new types of promotion they should concurrently develop internal standards for providing the PI (and, of course, fair balance).  In many cases those standards evolve over time for a particular medium but it is way better to have developed your company policy than to do nothing and wait to see what other companies are doing.   Or, you could just ask OPDP what they think!

Disease State Websites and Ads

NOTE: The opinions in this article are mine and are presented solely to cause thought on this subject and do not represent legal or regulatory advice.  Companies or individuals should seek appropriate legal or regulatory help to address these types of issues.

Information about a disease that is provided to consumers and/or healthcare providers has had many names over the years:  help-seeking ads, disease state ads, disease awareness ads, among others, have been used.  No matter what you call them, for a long time FDA has seen the advantages in drug companies providing useful, unbiased, non-promotional information to help educate patients and healthcare providers about diseases.   Likewise, pharmaceutical companies have long used these to raise awareness about a disease both with consumers and prescribers.   In most cases, and logically so, these companies have put their money into developing materials for diseases they have a treatment for. This has created the possibility for these disease awareness materials to be used as 'veiled' drug promotion. 

OPDP put out general  guidance in 2004 on this topic which was withdrawn by FDA in 2015.  To the best of my knowledge there has been no follow-up since that time.   Since the currently available, non-withdrawn documents from 1985 and 1988 are actually precursors to the 2004 guidance, there doesn't appear to be a lot of current, updated information.

From my experience and using the 2004 guidance as a source, I have constructed a series of dos and don'ts to keep your disease state materials pure and not product promotional.

DO

• Provide relevant, specific and useful information about the disease in question.  
• If directed at consumers, advise the consumer to go see an appropriate health care professional

DON'T

• Combine disease awarenss communications with mention or inference of a drug unless you also including fair balance and access to a product package insert (i.e., you are using disease awareness material within a product promotional setting)
• Make the design, images, color schemes, etc. between your disease awareness materials and product promotional materials be the same or similar
• Put disease awareness materials or ads near (or for multimedia, close in time) to product promotional materials
• Present information in such a way that it unduly scares consumers into going to their doctor or convincing them they have a disease because they have a particular symptom
• Present disease state information in an unbalanced way to imply that treatments can do more than they are approved to do (e.g., saying that treatment for diabetes will reduce the risk of heart attacks or strokes if the sponsoring company's diabetes treatment has not been shown to do that)
• Suggest self-diagnosis or suggest the use of unapproved testing as a definitive diagnostic test for the disease.
• In a situation where there are classes of drugs that treat the same disease, highlight the advantages or disadvantages of those classes, especially a class that a company's drug may fall under.
• If there is only one drug that treats a particular condition, discuss pharmaceutical treatment. (NOTE: A company MIGHT be able to include limited statements (e.g., 'this disease can be treated with exercise, pharmaceutical therapy or a combination of exercise and pharmaceutical therapy') about treatment of the disease.  It should be noted that this approach may entail some small risk based on the 2004 guidance and other things I have heard over the years.  Companies need to choose whether they are willing to accept this risk and, if they do, they must be careful on the wording they use when they mention that there is a treatment.  Any mention of treatment should also be in line with the approved indication.   For example, if a drug is approved to treat symptoms the language chosen should reflect that limitation).
• Provide disease state information on a disease that you do not have an approved indication for, especially if your drug is known to be used off-label to treat that condition and you do not have a drug approved to treat that disease.

Some things that I have learned over the years that might be helpful to people are as follows:

• OPDP Submission of Disease State Materials - Look, by definition you don't have to submit your disease state materials to OPDP.  However, I would consider submitting to OPDP your 'portable' (e.g., hard copy or flash drives) disease state materials.  In some cases these materials might up being used with promotional materials.  If submitted to OPDP with that intended use ('may be used in the future with promotional materials') it can help a company if the disease state materials are inadvertently used in the future along with promotional materials.  It also helps set up that these materials will be regulated internally.  
• Create an intended use for disease awareness materials - One thing that I have seen done over the years is that promotional materials can (and probably SHOULD) be approved with an intended use.  If they are used for something else this should involve a separate approval for the new use.   This same thought could be used for disease awareness materials.   If they are internally approved to be used alone, any use of them with promotional materials would have to be separately approved.  This would help to avoid situations where use of these materials could become problematic to the company. 
• Be careful about accidental connection between the drug name and the disease awareness materials - There has been some thought given to whether sales reps should be distributing solely disease state materials as the HCP likely knows that they promote a particular drug.   I have even heard of situations where a sales rep is wearing a nametag with the drug's name on it while presenting disease state materials or, in a laptop/tablet presentation, has the drug logo as their screensaver.  Also, if your website or printed materials cites references, make sure the titles of those citations do not mention or imply a particular drug or make claims about a drug class
• Links to product promotional websites from disease awareness websites - This is an interesting area.   Some companies believe that you should keep your disease awareness totally separate and don't allow links, even indirect ones, to promotional websites from disease awareness websites.   Some companies allow these links but the link (which may read something like "Click here to find out about a new treatment for disease XYZ") must pass through an intermediate webpage with a warning message (e.g., "You will now be redirected to a product promotional website.  Click here to go back to previous webpage").  OPDP has mentioned in at least one untitled letter that direct links between disease awareness websites and product promotional websites (no intermediate webpage) are not appropriate.  However, a few companies apparently still allow that.
• Disease awareness websites that have opt-ins to receive additional information - It is not clear how many companies have this.   However, my experience is that companies that do this do not allow product promotional information to be included in materials sent to people who opt in to receive disease awareness materials as that could be construed as veiled product promotion under the guise of providing disease awareness. 
• Other types of veiled promotion - Veiled promotion could include creating a search engine result that indicates directly or implies that the reader is going to be directed to a disease state website  when, in fact, they are directed to a product promotional website.   For example, such a search engine result could say something like "Click here to learn more about disease XYZ" and then direct someone to a product promotional website homepage. 

There are probably many more examples of gray areas that have come up over the years at drug companies about what are proper and improper disease awareness materials and the practices that surround use of these materials.  I just hope that the information above stimulates you to think about what is and isn't proper use of disease awareness materials.

Avanthi OPDP Letter

Just as you might have thought that the OPDP calendar year was going to go out like a lamb, the Office sent out their 4th letter (3rd warning letter) of the year, this one to Avanthi for their promotion of Lomaira (TM) at two meetings in early 2017.   Lomaira is manufactured by KVK Tech which has the same address as Avanthi Inc.   The relationship appears complicated as each of Avanthi and KVK Tech have separate ANDAs for this drug and it is unclear if KVK Tech was involved in the creation or use of these graphics, as well.

Warning Letter

Promotional material

The letter cites Avanthi for not providing ANY risk information on this graphic used at these two meetings.   It is not clear if these graphics are from booth panels for Lomaira for an Avanthi/KVK Tech booth at these meetings but it is reasonable to assume that this is the case. The company is also cited for not being clear about what Lomaira was indicated for, as the indication limited Lomaira to short term use in patients with certain body mass indices and/or co-morbid conditions.  As a warning letter it asked Avanthi to provide corrective information to all those who may have seen the booth panels which, for two national meetings of this size, would be quite extensive and expensive remediation. 

Given what is presented in the letter, it appears OPDP is standing on strong ground in citing Avanthi.  Clearly, limitations of the product are not captured on the graphic cited by OPDP and no ISI is presented on the graphic nor is the language on the graphic moderated in any way to take into account the approved product labeling. 

Interestingly, however, is that there is a product website for HCPs, https://www.lomaira.com/hcp/, which contains the same graphic but has the Important Safety Information (ISI) and other balancing information on the same webpage.  OPDP did not cite any of the information on this product website nor on a separate website, https://lomairaonline.com/ which may or may not be associated with Avanthi or KVK Tech but contains the same graphic and has claims about Lomaira but no safety information.  The boilerplate language in the OPDP letter covers OPDP from having to mention other uses of the supposed violative material but, generally, companies receiving OPDP letters immediately remove violative material from all sources following receipt of such a letter.  In this case, KVK Tech chose NOT to remove the graphic from its product website, possibly because the website contains the balancing information that the graphic at these conventions didn't have.   That is, they may have felt that the graphic was OK if the appropriate balancing information was presented in prominence similar to the graphic.

An interesting point that is worth consideration is whether Avanthi/KVK Tech had a booth at these meetings.  If not and this graphic was just presented in some rotating/flashing billboard in the main hall then OPDP's points are well-taken.  However, if this graphic was a booth panel at a product promotional booth at these meetings then the question remains why was there not ISI or balancing language associated with this graphic?  I have seen companies in the past use, for whatever reason, free standing ISI placards next to promotional graphics in a booth.  While I have seen these used they can be problematic as someone may forget to bring them or place them appropriately, they may be moved away from the graphic for some reason or they even may be obscured by desks, plants, etc., the latter having been cited before in OPDP letters.  Also, I have seen (very rarely) booths where the ISI is not on every booth graphic, which made me think that the company felt that the booth was one big promotional material and that they only needed to have ISI visible in the same prominence in some places in the booth to cover the claims they made throughout the booth. This would assume, of course, that the booth was always used in tact at all meetings.   It would be interesting if, indeed, these were booth graphics, to see what the overall layout of the booth was like and what the thinking of Avanthi/KVK Tech was in how they set up the booth and whether they had ISI. 

It would also be interesting to see who owns www.lomairaonline.com as, from the OPDP letter, one might have expected that website to be changed due to the OPDP letter and the lack of ISI/fair balance on that website.

Amherst Pharma/Magna Pharma OPDP Warning Letter

Author's Note: This is the official launch of this blog that will deal with issues impacting the marketing of pharma drugs, devices and combination products.   The opinions here are just those of the author based on my understanding of the area of drug and device advertising and promotion.

In Nov. 2017 OPDP issued a warning letter regarding the promotion of Zolpimist(R).  The letter was issued to the license holder for the drug, Magna Pharma, and its partner, Amherst Pharma.  The first thing that strikes me about this letter is that it is sent to the manufacturer and their partner, both of whom generated supposed violative materials.   We don't know if the promotional claims used by the partner were given to them by the manufacturer.   However, what we do know is that OPDP considers if a person or a company has a relationship with the manufacturer (e.g., KOL, distributor, partner, etc.) that this person or company is acting FOR the manufacturer.   Thus, the reason OPDP sent letters to both companies as both had violative claims.  This shows once again that market authorization holders need to monitor the companies or persons they are involved with to make sure those companies or persons are not doing inappropriate promotion of the drug involved.

This letter, the 3rd of the year by OPDP, contained nothing unusual besides the above.   The companies were cited for pretty standard violations:

• Failure to submit their promotional materials at time of first use
• Failure to include any risk information
• Overstating efficacy by language that would imply that Zolpimist, as a 505(b)(2) drug, was superior to the brand and generics containing the active ingredient zolpidem.
• Not providing material information.  For example, not providing the indication which would limit the time that this drug had been shown to be effective and indicating that there were no food effects with this mist when those effects were clearly listed in the label

So, what do we make of this most recent warning letter from OPDP?

Three things make it difficult to project the true meaning of any particular OPDP letter or series of letters:

• Context - was there any driving force (e.g., competitor complaints, previous communication by FDA with the sponsor, etc.) we don't know about that caused OPDP to single out this manufacturer for this promotion?
• Agenda - did any agenda at OPDP cause them to pick this drug class or this type of violation to cite?
• Background - did recent events and/or decisions on resource usage cause OPDP to pick out this type of violation?

For these reasons it is difficult to say if there is a pattern in ANY year of OPDP enforcement letters and particularly this year with only 3 letters being issued.  There could be any number of reasons for the issuance of this particular letter.  For example, there are so many competitors to Zolpimist that it is likely that one or more competitors, sensing the potential perceived advantage of the only zolpidem mist (vs tablets and sublingual) in this space, might have been keenly aware of Zolpimist promotion and complained to OPDP.   Considering that violations cited were in pretty public, easily accessible places (a website and a large convention) it is likely that these violations were seen by all these competitors.  So, potentially the weight of complaints might have been enough to get OPDP's attention and convince them to write this letter.

My opinion is, as Tom Abrams, the director of OPDP, has repeatedly said, is that Pharma is getting better at policing themselves in the area of ad/promo.  That being said, knowing the vast number of drug companies out there today, the competition within markets not only with generics but also with new brands coming to market and the number of new marketing areas being explored by drug companies, it seems obvious to me that there have been many potential violations reported to OPDP by physicians or advocacy groups (Bad Ad) or competitors in addition to those that were discovered independently by OPDP reviewers.   Yet, we only have 3 letters so far this year.

Another thought is that, given that there have been so few letters that have come out this year, it is possible that they all have something in common that OPDP is trying to remind us about. 

If there is a connection between these 3 letters, it is that they all mention not enough risk information.  The most recent 2 failed to include ANY risk information in their ads and the first one of the year, to Orexigen Therapeutics, cited specific risk information that had been omitted.  Omitting risk information is not, to my knowledge, something that has successfully been challenged in court as being a first amendment right so it still represents safe, low-hanging fruit for OPDP to write letters about that would be immune to court challenge.  Still, even if you believed this was true, you have to believe that more companies than Amherst/Magna and Cipher created and implemented materials this year that failed to provide ANY risk information this year and MANY more companies than the three cited this year that had insufficient risk information in their promotional materials.  This doesn't even mention those who failed to submit their materials at time of first use, although my hope is that this latter number was a couple of orders of magnitude smaller than these other potential violations.  So why were these three chosen?

I can't see any other obvious connection between these drugs or the type of promotion, or type of compliance letter sent that would link these letters together as some overall message by OPDP.    Even if that connection could be postulated, the small number of letters overall this year doesn't lend itself to any pattern being identifiable.

Finally, if you REALLY wanted to grasp at straws, one could postulate that the low number of letters this year could signal that the role of OPDP has, internally at FDA, been significantly redefined almost exclusively to one of education and prevention with only a really minor portion of its role being surveillance and enforcement.  Given that the environment in President Trump's administration seems to be more of helping pharma get new products approved faster rather than slowing anything about drug development or sales, this could be plausible, I guess.  However, any speculation that the current administration is stifling the issuance of compliance letters by OPDP for ANY reason would be very premature. 

The rest of 2017 and, indeed, all of 2018 will be interesting to watch to determine if 2017 is just an anomaly or if it signals a historic change in the role of OPDP.  "Experts" in this area have been chasing their tails for years trying to find patterns in OPDP letters and, for the most part, we have all come up dry.   While it makes for interesting and stimulating conversation if you are a regulatory ad/promo geek like I am, without sufficient information for the three bulleted things above, I don't know that we will ever know...and I am thinking that OPDP won't be opening their internal thinking process to any of us in the near future.  Their position has always been that the rules are out there, the rules are clear and all Pharma has to do is follow them to stay within the guard rails of appropriate promotion.  It's up to all of us to make sure that we effectively, yet appropriately promote our products.