As part of CBI’s Pharmaceutical Compliance Congress, Tom Abrams, director of the Food and Drug Administration’s (FDA) Office of Prescription Drug Promotion (OPDP), provided insight into his priorities areas for enforcement. He also touched on FDA’s draft social media guidance and on what information companies should expect in the near future. OPDP also hosted a separate “Enforcement Webinar” devoted to answering questions about why certain companies received OPDP Warning Letters. We gleaned a number of important takeaways from the two sessions.
As a background, the FDA tightly regulates pharmaceutical advertising. Companies are required to submit to FDA’s Office of Prescription Drug Promotion every promotional document—including printed, television, and website advertisements—at the “time of initial dissemination.” Each ad must contain a variety of elements, such as cited evidence for all claims, a “fair balance” of the benefits and risks of the drug, and any Black Box warnings.
Tom Abrams noted that “overall, promotional materials appear to be improving,” which he credited to the work and efforts by the FDA and industry. In 2013, OPDP received approximately 85,000 promotional pieces. However, there is work still to be done, according to Abrams. “Certain promotional proposals OPDP has received are concerning,” he stated. For some especially questionable promotion, he often wonders why a company is “even considering going down that road” when eventually, “it’s going to get the company in trouble?”
High Priority Areas for OPDP’s “Risk-Based Approach” to Enforcement
Abrams emphasized that the FDA has “zero tolerance” for companies who mislead patients or healthcare professionals (HCPs). He noted that OPDP continues to enforce through post-marketing reporting on FDA 2253’s, as well as conference attendance, complaints, HCP outreach through the Bad Ad program, and broad surveillance of materials. He explained that OPDP uses a risk-based approach to enforcement, in which his office targets promotional campaigns that have the potential to harm patients the most. He noted that “high priority” areas include (1) new products; (2) products with significant risks; (3) products cited for violations in past; (4) products cited in complaints; and (5) products with far reaching campaigns.
During the separate OPDP Webinar, in response to a question about whether OPDP targeted products with black box warnings, OPDP stated that it uses its risk-based approach, and does not specifically target black box products. The question noted that from July 2013 through December 2013, 50% of regulatory letters were for products with boxed warnings.
The most common violation in 2013 was for companies who omitted or minimized the risk of their product. Abrams also stated that misleading superiority claims are “not fair” for companies to make when they cannot support the claim.
In a separate conference, Sheetal Patel, Regulatory Compliance Lead for Johnson & Johnson International, presented an enforcement overview on the number of disciplinary measures that focused on digital violations.
Social Media
The digital violations in the chart include promotion via emails and websites, but the FDA has not yet enforced a social media violation. Part of this has to do with the fact that companies have been wary to even enter the medium without an idea of how the FDA will approach violations. With the rapid increase of promotion through real-time social media outlets, pharmaceutical companies have to worry about how to properly follow the regulations in the real-time communications. Interactions by tweet or Facebook post, for example, can be uploaded instantly, in large quantities, and, on Twitter at least, in a maximum of 140 characters. Those limitations require a creative mind to incorporate a “fair balance” of information about a drug.
Earlier this month, we discussed the long awaited FDA social media guidance. Abrams noted that the recent social media guidance is “not the only one,” and that more will be “coming shortly.” He noted that the guidance addresses factors taken into consideration to determine if product communications using interactive media are subject to FDA post-marketing. With respect to submission of social media materials, Abrams stated the guidance “makes sense,” but noted that it was just the agency’s “thinking,” and not a regulation. Abrams noted that OPDP is still working to develop internet and social media guidance, including addressing space and character limitations. The FDA is also working on guidance for best practices to correct misinformation on third-party sites.
OPDP’s Other Projects
Abrams also discussed the November 2013 Guidance regarding product name, placement, and size. He noted that the established name must accompany the proprietary name at least once per page or spread, and must appear where the proprietary name most prominently appears on page or spread. He also stated that the use of the established name in running text or columns must appear only once per page, and does not have appear in each column.
In the context of websites, Abrams explained that established names on web pages or electronic screens do not have to be repeated and need only appear once per page in a prominent location. He noted that a “page” depends on the monitor size, but OPDP says to think in terms of “8 x 11” printed page.
Abrams also noted that OPDP is revising current guidance, including Disclosing Risk Information in Consumer-Directed Print Advertisements, and Presenting Risk Information in Prescription Drug and Medical Device Promotion.
Warning Letters
One speaker a senior compliance counsel at a midsized pharmaceutical company spoke at the Compliance Congress about how FDA Warning Letters, despite their name, have moved beyond mere “warnings.” According to the speaker, companies should be very concerned once they receive a letter. A warning letter can be used to build a case around improper promotion for plaintiff’s attorneys, and the Office of the Inspector General and state attorney generals quickly add them to their investigation files. They noted a recent example of Aegerion’s CEO conducting what the OPDP considered an “unbalanced interview.” Within seven days of the broadcast, Aegerion received a warning letter. The Justice Department subpoenaed the company just a few months after the interview.
OPDP Webinar on Warning Letters
On January 30, one day after Abrams presented on behalf of OPDP at the Compliance Congress, FDA hosted an Enforcement Webinar that discussed specific Warning Letters. We have provided links to the letters at issue in each question.
Question: Why did Soltamox get a Warning Letter? Was it based solely on the omission of risk?
Answer: The omission of risk was not dispositive of getting a Warning Letter, and no single factor determines this. FDA will consider (1) the nature of the violation and how egregious it may be; (2) the magnitude of impact on public health; (3) the need for corrective action; and (4) repetitive violations.
Question: How was the omission of material fact in the Aranesp direct mailer misleading?
Answer: OPDP noted that the direct mailer failed to provide additional information on approved dosing. OPDP noted that the FDA-approved product labeling (Pl) provides extensive instructions that are material for dosing (e.g., discarding dose, different dosing schedules, monitoring requirements, and instructions for subsequent dosing in hemoglobin level).OPDP noted that omission of this information was material because it isimportant for HCPs to have this information so that HCPs may consider it when determining appropriate dosing.
Question: Why was there a letter for the use of a bar graph regarding level of blood pressure reduction for Benicar? (The promotional piece included an open label trial for this graph; however, the material also included a note that the results of the open label trial were different than the main pivotal study).
Answer: OPDP stated that the use of the bar graph referencing the open label trial was improper because the trial was open label and uncontrolled and therefore did not provide adequate evidence for this claim. OPDP noted that the open label trial lacked blinding and a placebo group that could result in bias. OPDP also noted that the open label trial did not account for all relevant subgroups. As a result, the open label trial cited did not constitute substantial evidence to support the efficacy claims cited. OPDP also noted that the footnote disclaiming the results of the open label trial was not sufficient to mitigate the risk of this information.
Question: Why were the claims in the Brovana materials regarding superiority improper, as the Warning Letter stated?
Answer: OPDP noted that the claims made in the promotional materials were not supported by substantial evidence, and there was no head-to-head clinical studies done for this purpose. OPDP noted there was no study done on the administration method for the superiority claims made. OPDP noted that the claim “time on your side” was misleading because it suggested faster time for the medicine, which was a superiority claim that could only be made with substantial evidence.
Question: Why did Ampyra receive a Warning Letter?
Answer: FDA restated that it considers several factors, but noted that it had issued an NOV letter in June 2012 for a similar violation, and that the recent violation omitted serious risk information that should have been conveyed. Thus, there was a need or corrective action because of the significant impact on public health.
Question: Why did Vascepa get an NOV letter when it contained claims consistent with the PI?
Answer: The piece did not contain or communicate serious or common risks.
Question(s): Why did Ribasphere get a warning letter?
Answer: The promotional material omitted risks. OPDP noted that although there was a separate page of IS, there was no risk information provided in the body of the letter. Because the body of the letter included efficacy claims, but no risk, OPDP said the material was misleading.
With respect to adherence, OPDP also noted the piece was misleading because it was not supported by substantial evidence. Claims that a product improves adherence imply a treatment benefit, which must be supported by substantial evidence OPDP stated. They noted that adherence takes into consideration multiple aspects of efficacy, dosing, convenience, and cost–which all require adequate and well controlled trials, using well development instruments that can assess adherence to treatment to support such claims.
Question: NOV letter objected to omission of material fact because it failed to include limitations listed under indication.
Answer: OPDP noted that the piece was violate because it did not include the limitations of use. The full PI includes the limitation of use, and such limitation is “material information” related to the drug indication.
Question: Does a letter to Zevalin, an orphan drug, suggest targeted enforcement?
Answer: No. Similar to black box answer above. OPDP uses a risk-based enforcement approach and does not target specifically orphan drugs.
Question: Why was there an omission of risk claim for Lanoxin when there was two paragraphs of risk information and a directive to see the full PI?
Answer: The two-page letter had numerous efficacy claims, however the letter failed to disclose serious risk:no contraindication, as well as serious precautions, adverse events. OPDP noted, however, that the letter “prominently had efficacy claims in the body of letter.” OPDP also noted that safety information was included after the signature block and on the back of letter. OPDP stated that risk information must have comparable prominence and readability as efficacy claims.
Question: How did FDA become aware of the Ampyra promotional material that was published in the Illinois Register?
Answer: OPDP received a complaint.
Question: Why did Cedax get a regulatory letter?
Answer: Cedax’s webpage was missing dosing information. The webpage presented dosage of 9mg/kg, however, the webpage ommitted material information, such as the maximum dosage, dosage frequency and duration, and other considerations. OPDP noted that FDA regulations require promotional materials to include relevant information. Thus, OPDP noted that the piece omitted material facts by not having all dosing information.
Question: Why did Lanoxin get a regulatory letter?
Answer: OPDP noted that the narrow therapeutic index referenced in the piece was not the specific claim that triggered a letter; it was the totality of the presentation that had misleading superiority claims.
Question: Why did Zevalin get a letter?
Answer: The piece omitted material facts. The piece included reference to 12.1 months versus 10.1 months. OPDP noted that statistical significance is critical for HCPs to determine study results. While the claim made about months was accurate, the difference was not statistically significant–the median in progression could have been due to chance alone, not the result of the drug.
Notably, when asked about why FDA sent a Warning Letter for Juxtapid when the CEO’s comments on Fast Money were towards investors, FDA paused for several moments, said it would come back to the question, and never answered the question.
___________
In their presentation at the Compliance Congress, the same speaker emphasized their serious disagreement with the public, and FDA, perception that healthcare companies have a motivation to “underreport” adverse effects of their drugs. “Is that the general ignorance of American public about trials?” they asked. With the new Sunshine Act requirements and Clinical Data Transparency, both of which focus on transparency, he hopes that the FDA becomes more flexible in the speech it allows.
If full data is more accessible, he argues, what do companies have to hide?
Policy and Medicine will continue to post updates about OPDP enforcement actions and any social media guidance down the road.