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.