Enforcement Update from OPDP

By Julie Tibbets posted 30-Jan-2014 19:30


Summary of OPDP Enforcement Update Webinar – January 30, 2014


Participants from OPDP/FDA: Bryant Godfrey, Senior Lead Regulatory Counsel; Julie Chronis, Regulatory Counsel; Robyn Tyler, Regulatory Counsel; Cynthia Ng, Regulatory Counsel; Kaylynn Yoon, Regulatory Counsel


Today's enforcement update webinar from the U.S. Food and Drug Administration's (FDA's) Office of Prescription Drug Promotion (OPDP) covered Warning Letters and Untitled Letters issued from July 2013 through December 2013 by OPDP (a total of 14 letters; 3 Warning Letters and 11 Untitled Letters).  Among these, 2 letters were issued to ANDA manufacturers; 2 to BLA manufacturers; and 10 to NDA manufacturers.  Notably, 7 of the 14 letters were issued to companies with products carrying boxed warnings – that is, OPDP dedicated 50% of its enforcement activity in the second half of 2013 to products carrying risks that included boxed warnings.   As you will see below, OPDP dodged a question regarding the letter it issued on statements made during a CNBC investor-focused broadcast and whether that was rightfully within OPDP’s jurisdictional promotional purview.  As such, that remains an area open to debate.  Following is a summary of the content of today’s webinar:


OPDP presented a summary slide noting that the violations cited in the letters issued in the second half of 2013 included: promotion of an investigational new drug; omission/minimization of risk information; unsubstantiated superiority and misleading claims; overstatement of efficacy; omission of material facts; and minimization of risk information.  [As a side note, we could not identify which letter issued in this time frame related to the promotion of an investigational product.]  Next, OPDP proceeded to the Q&A portion of the webinar:

  • A question was asked on how 50% of letters issued in the second half of 2013 related to boxed warning products. OPDP said that it does not target boxed warning products but said that it has to prioritize its efforts based on risk to the public health.
  • Why wasn’t the Soltamox letter a warning letter since there was an omission of risk section? OPDP said that it considers a number of factors in deciding whether a letter should be an untitled vs. a warning letter and no individual factor such as omission of risk information will be dispositive of issuance of a warning letter. OPDP said it looks at repetitive behavior among other factors.
  • The Aranesp untitled letter cites the direct mailer for omission of material facts yet the letter confirms that the mailer was consistent with the every 3 week dosing of the PI. OPDP said it was accurate to state that dosing was every 3 weeks but the letter failed to provide any additional dosing information regarding Aranesp despite the extensive dosing information – starting dose, monitoring requirements, dosing schedules, subsequent dose adjustments, etc. – provided in the PI. OPDP said that was important information for HCPs to have when considering how to appropriately dose Aranesp.
  • For the Benicar untitled letter, the material was found misleading because it portrayed blood pressure reduction in a manner OPDP found inconsistent with the PI or misleading even though it also presented the findings in the pivotal trial. OPDP said that the claim references an open-label trial; it lacked blinding and a placebo control group which can introduce a bias. OPDP said this type of trial does not constitute substantial evidence to support the blood pressure reduction claim. OPDP further said that it did review the data presented in the note below the bar graph stating that the findings were different than in the pivotal but said that the note did not mitigate the misleading information.
  • For the Brovana untitled letter, why aren’t comparisons to an active control in a clinical trial sufficient to support the claim. OPDP said there were claims that Brovana was clinically superior to other COPD medications, which requires adequate and well-controlled trials with other products; however, OPDP said the trials were not designed to examine superiority here. In addition, the claims about manual dexterity would have to be supported by substantial evidence and they were not so they were also misleading.
  • Revonto can be constituted in 20 seconds, so what is wrong with saying Revonto puts time on your side, etc.? OPDP said that this implies that this feature makes Revonto a better product with better clinical outcomes requiring the support of head-to-head clinical trials, which support was not presented here.
  • For the Ampyra letter, why was that letter issued as a warning letter? OPDP said it evaluates numerous criteria when determining whether to issue a warning letter. OPDP issued a letter in 2012 (untitled) to the company for similar issues. Given the significant impact on public health, OPDP felt a warning letter was appropriate here.
  • The Vascepa print invitation contained claims consistent with the PI yet the sponsor still received an untitled letter – can OPDP explain? OPDP said that the piece contained representations about the use of Vascepa but did not contain or communicate the most serious risks associated with the use of Vascepa.
  • For Ribasphere’s warning letter, the company was cited for omission of risk information in a letter despite an entire page of risk information being included. Can OPDP explain? OPDP said that because the letter omitted risk information in the body of the letter, that the inclusion of risk information outside the body of the letter did not mitigate the omission of risk information in the body itself.
  • Why were Ribasphere claims regarding adherence misleading? Claims that Ribasphere will improve treatment adherence is a claim requiring substantial evidence as demonstrated through adequate and well-controlled trials using well-developed instruments that can adequately assess patient adherence to treatment.
  • The Diclegis untitled letter included the omission of material fact because the promotional material failed to include the limitations of use in the PI – i.e., Diclegis has not been studied in certain women. OPDP said that the limitations of use is material information and should be included in the piece.
  • For the Zevalin untitled letter, it was designated an orphan drug by FDA; does this letter show an increased interest by OPDP to target orphan drugs? OPDP said similar to boxed warning products, OPDP does not target specific designated products such as orphan products but instead takes a risk-based approach in its enforcement actions.
  • For the Lanoxin untitled letter, the 2 page physician letter included 2 paragraphs of risk information with a direction to see additional risk information on the reverse side; why did OPDP cite this company for omission of risk? OPDP said that the letter completely omitted contraindication and serious adverse events, but noted that the safety information included was included after the signature box. OPDP said the risk information should have been included with a comparable prominence to the efficacy information.
  • · For the Juxtapid warning letter, why are statements made on a show targeted to investors cited in the letter? OPDP – after a long pause – said it will have to come back to this question (but note that OPDP never did return to this question).
  • For the Ampyra warning letter, the promotional piece was published in an Illinois register, how did OPDP become aware of the print ad? The print ad was submitted to OPDP as a complaint, according to OPDP.
  • For the Cedax untitled letter, the letter cites missing dose information – why? OPDP said the webpage presented the dosage recommendation of 9 mg/kg but omitted information such as maximum dosage and other considerations.
  • For the Cedax untitled letter, why was the failure to include the indications/usage section an omission of material facts? OPDP said FDA regulations state that materials are misleading if they omit material facts. Any “Note” related information related to the indication section of the PI should be presented so as to avoid the misleading omission of material fact.
  • Explain the citation of failure to include established name in the Diclegis untitled letter. OPDP said the print ad did not include the established name. OPDP directed the audience to its guidance on presentation of established name.
  • The Lanoxin physician letter included a claim regarding change in pharmacodynamic response, explain how this claim suggests that Lanoxin is superior in safety/efficacy to generic formulations? OPDP said it was the totality of the presentation including the claim regarding the narrow therapeutic index that made the presentation a misleading superiority claim.
  • For Zevalin, the untitled letter cites Spectrum for omitting material facts in making a statement regarding the statistical significance where the statement made was in fact accurate? OPDP said that the claim, while accurate, failed to state that the time to progression was not statistically significant which may/may not mean the results were attributed to the treatment effect of the drug.
  • OPDP abruptly ended its webinar without returning to the earlier CNBC question and said further questions could be directed to OPDP’s email question inbox.

Julie Tibbets is a partner in the Food, Drug & Device practice at Alston & Bird LLP where she focuses her practice advising manufacturers and marketers of drugs, biologics, and medical devices on marketing, medical affairs, and health care professional related interactions as well as Sunshine Act compliance. This posting 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 julie.tibbets@alston.com or at 202.239.3444.