Today, the U.S. Food and Drug Administration’s (FDA’s) Office of Prescription Drug Promotion (OPDP) held its semi-annual update on enforcement actions occurring in the past 6 months. OPDP attendees included: Robert Dean, Director, Division of Consumer Drug Promotion; Andrew Haffer, Director, Division of Professional Drug Promotion; Bryant Godfrey, Regulatory Counsel Team Leader; Cynthia Ng, Regulatory Counsel; Robyn Tyler, Regulatory Counsel; and Ernest Voyard, Regulatory Counsel. Robyn and Ernest fielded most questions regarding OPDP’s recently issued letters covering the following products: EpiPen, Incivek, Sodium Ferric Gluconate Complex, Kepivance, Zmax, Xenazine, Ampyra, Equetro, Ixempra, Zovirax, Daliresp, Amyvid, FazaClo, Vantus, Tarceva, Infasurf, Curosurf, and Patanase. The most common violations noted in these letters continue some recent trends and include some less common violations as well: omission/minimization of risk information; unsubstantiated claims and superiority claims; overstatement of efficacy; omission of material facts; broadening of indication; inadequate communication of indication; promotion of unapproved uses; inappropriate reminder labeling; misleading claims/presentation; failure to fulfill “adequate provision” requirement; failure to submit under a Form FDA-2253; and inadequate presentation of established name.
Following is a summary of the question and answer portion of today’s webcast that addressed industry’s questions on recent OPDP actions:
(1) Curosurf: Since the enforcement letter acknowledges that the press release accompanies the pitch letter, what was the rationale for determining that the promotional pitch letter, itself, must include risk information? OPDP said while the letter and press release were intended for distribution together, each is a standalone material and, as such, is required to contain risk information.
(2) Xenazine: If a video is embedded on a web page in a manner that allows the user to also see the risk information/disclosure on the web page, is the risk disclosure still required in the video itself (contrast this to a scenario where the video pops up in a new video and fills the entire space)? OPDP said that when an embedded video appears on a separate screen, fair balance must be provided. With respect to a video embedded within a page that houses a risk disclosure, OPDP said that it would look at how much risk/benefit information is in the video itself vs. on the web page and would also look at whether it is in its own window or not. OPDP said in situations like this that it would like to see the sponsor submit the material for advisory comments from the agency.
(3) Zovirax: Why did this letter not go to GSK? It is addressed to Valeant Pharmaceuticals. OPDP said that at the time the letter was issued, Zovirax was marketed on a website that Valeant Pharmaceuticals was operating.
(4) Incivek: Since James was a patient treated with Incivek, why was it misleading to feature James? OPDP said James was not a typical patient; he was from the subset of patients that is most difficult to treat. Also, the sponsor did not present the response rates in that population which were significantly lower than in other populations.
(5) Incivek: The incivek sponsor was cited for minimizing a risk not included in its product labeling; how is that possible? OPDP said that Incivek is not a monotherapy and alopecia was a common adverse reaction for the therapies with which Incivek must be prescribed. The Incivek promotional material had a story with the statement that “When the side effects kicked in, I got a rash and lost some hair, but that was nothing,” thereby minimizing the risk of alopecia associated with Incivek combination therapy.
(6) EpiPen: Why was a teleconference needed prior to issuing the EpiPen warning letter, and why was the letter still issued after the sponsor agreed to comply with the request to pull the advertisement? OPDP said that when misleading promotion occurs, OPDP may call a sponsor in advance of issuing a letter if there is a public health issue associated with the promotion. However, at the time a call is made, the letter is already in progress. OPDP noted that a call similarly was made prior to issuing the Amyvid untitled letter.
(7) Ampyra: How come the risk information in the video was not adequate? OPDP said that the risk presentation in the video was not adequate because it failed to disclose some of the serious risks associated with Ampyra. The part of the video featuring an interview between a patient and doctor focused on the benefits of Ampyra but the “telescript” provision of risk information was not a comparable presentation in prominence to the benefit presentation.
(8) Ampyra: If a promotional piece presents actual patients and their experience with a therapy, why does OPDP find it misleading? OPDP said that patient testimonials are still considered promotional, so any claims made in patient testimonials need to be consistent with the product’s FDA-approved labeling. OPDP explained that you cannot go beyond the scope of the FDA-approved prescribing information; with Ampyra, the approved prescribing information discusses improvement in walking with multiple sclerosis patients demonstrated by an increase in walking speed. In the Ampyra video, the patient discusses less of a need for using her cane. OPDP said that this was an overstatement of efficacy because the Ampyra approved prescribing information only discusses increased walking speed and walking improvement and does not discuss less of a need for walking-assisted devices.
(9) Tarceva: Was the development of a Grade 2 rash really being suggested as a benefit – e.g., can a side effect be presented as a sign that a product is working? OPDP said that the presence of a rash as associated with improved survival was based on a retrospective, exploratory analysis. OPDP said that the related statements minimized the risk of Tarceva by suggesting that there was a clinical benefit to the appearance of a rash for improved survival. Also, OPDP noted that the retrospective nature of the data caused the study findings to lack substantial evidence.
(10)EpiPen: Why was the warning letter issued to Pfizer if the advertising was produced by Mylan Specialty? OPDP said that Mylan Specialty, L.P. had a license to market, sell, and distribute EpiPen but the license to do so was issued by Meridian Medical Technologies, Inc. which is a Pfizer subsidiary.
(11)OPDP noted in the EpiPen warning letter that the TV advertisement complaint was submitted through the Bad Ad Program – are complaints submitted through the Bad Ad Program coming from consumers or health care professionals or both? OPDP said that it has received numerous complaints through the Bad Ad Program and although the purpose of this Program is to reach out to health care professionals, OPDP also receives complaints through this Program from consumers and patient advocacy groups as well. OPDP did not identify the source of the EpiPen Bad Ad complaint.
(12)Were there any trends noted in this batch of enforcement letters - anything in particular OPDP would like to see industry do to improve compliance? OPDP said that there were no specific trends noted in this batch of letters. OPDP said that it recommends sending in materials for advisory comments if industry members are making a new claim in promotion or launching a new campaign based around new claims. OPDP encouraged industry to reach out to its OPDP reviewer in these instances.
(13)Sodium Ferric Gluconate: Why did FDA refer only to this product’s established name throughout the letter? OPDP said that there was not an approved name yet for this product, so that is why OPDP used the established name.
(14)Can an AB-rated drug make claims based on studies even if those claims are based on studies beyond those included in the approved prescribing information? OPDP deferred answering this question.
(15)Daliresp: What documentation does OPDP require in order to support a complaint regarding oral statements to the Bad Ad Program? OPDP said that it takes a broad approach to complaints that come into the Bad Ad Program and reviews those complaints together with other complaints/information that FDA receives in order to determine whether a complaint has merit. OPDP also verifies whether information in complaints is accurate and said that OPDP needs to get comfortable that what is alleged to have occurred actually occurred before moving forward. OPDP does not rely on “he said/she said” information when taking enforcement action.
(16)Kepivance: Is the content of a daily diary questionnaire used in a study considered appropriate evidence to support quality of life claims and, if not, what would be adequate to support quality of life claims? OPDP said claims on a website related to eating, talking, drinking, and swallowing require substantial evidence based on adequate and well-controlled studies using validated instruments. So, OPDP explained that, in this case, the content and validity of the daily diary had not been established. OPDP said that if sponsors want to make quality of life claims, that sponsors should discuss plans for doing so with the review division early on in the process.
(17)Equetro: Can a sponsor support a claim about weight maintenance in patients receiving bipolar disease treatment? OPDP said that, here, weight management was not a primary endpoint in any of the studies for Equetro, so it was not appropriate to make claims about weight management. If sponsors have substantial evidence about weight management or loss, OPDP says that sponsors should submit that information for advisory comments.
(18)Zmax: The Zmax promotional piece presents risk information with the same prominence as efficacy information, how did OPDP justify a prominence and readability violation in this letter? OPDP said that efficacy claims in the promotional material had prominent/colorful headers and were surrounded by lots of white space, in contrast to risk information which was in block form with no bullets, no white space, and no headlines to separate it from the efficacy information. In addition, OPDP said that some risk information even appeared under efficacy headlines, so the risk presentation was not comparable to the benefit presentation.
(19)Ixempra: OPDP often objects to claims based on retropsective analyses. Why does OPDP also consider claims from a prespecified analysis misleading? OPDP responded that, here, “prespecified” was misleading because OPDP did not consider stable disease to be a valid endpoint.
(20)Ixempra: Why are exploratory analyses and poster presentations not considered substantial evidence and what would constitute substantial evidence? OPDP responded that double-blind, well-controlled studies, generally, constitute substantial evidence except where there may be an ethical problem with designing such a study.
(21)Daliresp: What would be considered an adequate presentation of the indication for Daliresp? OPDP said that the full, approved indication should always be presented, including any limitations of use – e.g., limitations based on use in certain patient populations.
(22)Daliresp: Regarding the minimization of risk information, why can’t sales representatives present and discuss the feedback that they have received from health care professionals about the drug? OPDP said that, here, the sales representatives used the feedback to downplay the risks associated with the drug. So, OPDP said that while it may be actual feedback, any use of that feedback should be in line with the approved labeling. OPDP noted that its approach here is very similar to its approach with patient testimonials.
(23)Zmax: Zmax was cited for broadening the indication for the drug, what factors did OPDP use to determine that the promotion went beyond the approved indication? OPDP said that it looked at what was not said in the promotional material. OPDP said that the promotional material made the product’s use sound broader than it is – e.g., suggested use in treating a viral infection when it is only approved to treat bacterial infections.
(24)Zmax: The Zmax letter objected to claims made on survey questions – are surveys ever considered acceptable to support claims and, if so, what types of claims? OPDP responded that surveys may be used for claims that may not be clinical or imply treatment benefits. If the claim the survey supports is nonclinical, then OPDP said it could be permissible. OPDP explained that the type of evidence and type of claim are key factors in its review. OPDP recommended that sponsors submit draft materials with claims based on survey data for advisory comments prior to using survey results in promotion.
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Please let me know if you have any questions regarding today’s webcast.
Julie Tibbets is a partner in the Food, Drug & Device practice of Alston & Bird LLP where she focuses her practice on advising clients on compliant product promotional materials and activities.