Today, the U.S. Food and Drug Administration's (FDA's) Office of Prescription Drug Promotion (OPDP) held a webinar to provide an update on enforcement actions it has taken in recent months. Among the main takeaways from today's meeting are that risk information presentation continues to be a problem area for many companies due to lack of prominence, lack of sufficient risk disclosures, and inequality in graphic/visual presentation of efficacy claims vs. risk information. OPDP also noted that keywords companies use for internet promotion purposes do not have to submitted on Form-2253 submissions. Representatives from OPDP noted that FDA is continuing to work on social media guidance and is considering comments it has received on the need for preapproval promotion guidance. Finally, OPDP stopped short of saying that meta-analyses could never be appropriate support for an efficacy claim, stating instead that meta-analyses generally do not constitute substantial evidence (going around the question presented, which asked whether there is ever a case in which a meta-analysis could support an efficacy claim in promotion).
Following is a complete meeting summary:
Highlights of OPDP Enforcement Action Update – July 29, 2013
- OPDP Presenters/Participants: Bryant Godfrey, Senior Lead Regulatory Counsel; Julie Chronis, Regulatory Counsel; and Robyn Tyler, Regulatory Counsel
- FDA apologized for the enforcement update webinar technology glitches it has been experiencing. Feedback on the webinar can be directed to: CDEROPDPenforceweb@fda.hhs.gov.
- 7 letters were issued by OPDP, all untitled letters, from April to June 2013: Clozapine, CBT-1, Mitosol, Marplan, Oncaspar, Doxil, and Xarelto. Links to these letters and corresponding promotional materials can be found at: http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/EnforcementActivitiesbyFDA/WarningLettersandNoticeofViolationLetterstoPharmaceuticalCompanies/ucm339597.htm.
- Violations cited included: promotion of investigational new drug, omission/minimization of risk information, unsubstantiated superiority claims/misleading claims, inadequate communication of indication, etc.
(1) Questions Specific to Individual Letters
- Clozapine letter: The article detailer included risk information on the back page; why does sponsor need to include more risk information in a 4 page brochure, article detailer? OPDP said some of the serious risks were omitted and some material information needed to adequately detail each risk was not presented. For example, the brochure stated that the drug was contraindicated with certain drugs but without specifying which drugs despite the potentially fatal adverse reactions possible with those contraindicated drugs.
- Clozapine letter: The letter objected to claims found on the reprint carrier itself that were supported by the accompanying reprint. Can OPDP share any thoughts on this? OPDP said that to the extent a reprint contains information about off-label uses, OPDP directed the questioner to the reprint guidance and its dissemination recommendations.
- CBT-1 letter: OPDP has said that investigational uses can be discussed so long as the claims are qualified. How come OPDP included some of the qualified claims in the CBT-1 letter? OPDP said that the overall net impression of claims regarding CBT-1 was that the drug is safe/effective for the claims stated. OPDP said that there were numerous conclusory statements in the presentation even if a few of the claims were qualified.
- CBT-1 letter: Is the agency planning to issue guidance to help companies avoid being the target of preapproval promotion? OPDP said that it has issued a few letters recently on preapproval promotion that should be instructive. Also, OPDP said that it received a citizen petition addressing the issuance of preapproval promotion guidance and stakeholders have submitted comments on this petition. FDA said it will take these into consideration and no decision has been made.
- Mitosol letter: Why did OPDP object to the omission of risk information on a 1-page piece? OPDP said that, for example, the piece omitted dosing information with the claim “assured dosing” despite how there are additional dosing considerations and information in the Mitosol label.
- Mitosol letter: Why was the “1-877-EYE-MITO” number cited in the letter? OPDP said that the phone number included “EYE” which made a representation about the use/effectiveness of the product, triggering the need for the full indication and risk information.
- Mitosol letter: This piece omitted the product indication and risk information – why was this an untitled letter and not a warning letter? OPDP said that while these were omitted, it considered the egregiousness of the violations, the magnitude of the impact on the public health, and whether or not this was repetitive conduct on behalf of the sponsor. After considering these and other factors, OPDP said that it determined an untitled letter was warranted.
- Marplan letter: Is there ever a case where a meta-analysis could be used to support claims of efficacy in promotional materials? OPDP said meta-analyses are generally not substantial evidence to support claims of efficacy. In this case, OPDP said the meta-analyses were based on a literature review that may have produced a biased sample of studies. In addition, OPDP said the underlying studies were conducted with different doses and varying clinical conditions.
- Marplan letter: How did the presentation on the health care professional webpage cited in the letter minimize the risk information? OPDP said that the efficacy information was presented at the top of the page in colorful graphics, etc., whereas the risk information was presented below the references at the very bottom of the page. Here, OPDP said the overall presentation minimized the risk information; the risk presentation was not prominent.
- Oncaspar letter: The letter states that the promotional piece made a misleading claim about the duration of therapy. The label does not indicate a duration of therapy. Can OPDP explain? OPDP said that it failed to disclose that the duration of therapy could be limited by various dose limiting factors/toxicities.
- Oncaspar letter: The material features a geriatric patient on the cover – why did FDA object given the material disclaimed on the back cover that Oncaspar clinical studies did not include sufficient numbers of subjects 65 years of age and older? OPDP said that the picture was not representative of the patient population treated in the supporting studies noting that the picture did not convey the material fact from the label that the drug has not been studied in subjects aged 65 and older (the disclaimer on the back cover did not mitigate the misleading impression made by the photo and “no age restrictions” claim in the sales aid).
- Doxil letter: Was the information provided on the website regarding use of the biomarker in patients receiving Doxil inconsistent with the literature? OPDP said that there is conflicting data in the literature and that the chart review data and other data referenced were not substantial evidence to support the claims made.
- Doxil: What is known about the use of CA-125 from the clinical studies provided in the approval of Doxil? CA-125 was a baseline demographic used in the studies. It was not evaluated for treatment response or monitoring; therefore, any claims associated with that are considered unsubstantiated.
- Xarelto letter: The letter indicates that the risk information was minimized despite how risk information was presented on an adjacent page and prior to the presentation of efficacy claims. How is this problematic? OPDP said the risk presentation was not prominent in this case. Regarding how OPDP evaluated the presentation, OPDP said that the risk information was presented on the adjacent page and without similar graphic presentation or colors to draw the reader’s attention, thereby misleadingly minimizing the risks presented. OPDP further stated that the content did not visually appear to be connected to the efficacy spread.
- Xarelto: This letter included an objection for the claim “and there are no dosage adjustments” as it implied no adjustments may be necessary. Can you explain why this objection was included in the letter? OPDP said this objection was included because although Xarelto does not need to be adjusted based on coagulation tests, it does need to be adjusted based on renal impairment; therefore, to claim that there are no dosage adjustments associated with Xarelto is misleading.
(2) Miscellaneous Questions
- Why does it take OPDP so long to issue enforcement actions – what if a company has already stopped using the piece? OPDP said all letters are well-vetted, requiring several layers of review which impacts the timing of issuing an enforcement action. If a company has stopped using a piece, OPDP would still issue a letter because people were exposed to the violative promotion and corrective information may be warranted. Also, OPDP said it would still issue the letter because the company may be disseminating similarly violative materials.
- What can companies can do to ensure compliant promotion? OPDP said that companies can review letters OPDP sends to other companies and associated promotional materials both of which are posted online. OPDP said that FDA also has guidances available on the FDA website on relevant topics. Finally, OPDP suggested the submission of promotional materials for advisory comments whenever a company has questions.
- If a company requests advisory comments on a non-launch advisory piece, what is the timeline for OPDP to provide comments? OPDP said that launch promotional materials are considered “high priority” for review whereas non-launch materials are reviewed as workload allows. However, OPDP said that its reviewers try to review non-launch materials as expeditiously as possible.
- Do companies have to submit keywords (assume meta data) used for internet promotion via 2253 submissions? OPDP said keywords do not have to be submitted on 2253s.
- What about price catalogs – do these require 2253s? Yes, OPDP said these are listed on Form-2253 as requiring submission.
- Were any of the letters issued April to June based on Bad Ad Program complaints? No, OPDP said that none of its recently issued letters were based on Bad Ad Program complaints.
- How long can companies use the phrase “Now available” in promotion? OPDP said phrases like “now available” or “new” should not be used for longer than 6 months from the time the product is initially approved.
- Is social media guidance coming soon? OPDP said this is a high priority within the agency with dedicated resources moving this along, but that no time line can be indicated at this time.
- Is there any type of appeals process if a company receives an untitled or warning letter? OPDP said that what happens after receipt of a letter is that OPDP will engage in further communications with the company and if the company disagrees with OPDP, the agency will attempt to resolve the matter at that level.
- Can you give guidance about what FDA would consider an on-label reprint? OPDP said that an on-label reprint would be one that is consistent with the Prescribing Information or one containing substantial evidence to support the claims being made.
Julie Tibbets is a partner in the Food, Drug & Device/FDA Practice of Alston & Bird LLP where she focuses her practice on advising manufacturers of drugs, biologics, and medical devices on marketing, medical affairs, and health care professional related matters and interactions. This publication is intended to be informational and does not constitute legal advice regarding any specific situation. This material may also be considered attorney advertising under court rules of certain jurisdictions. Julie can be reached at email@example.com or at 202.239.3444.