OPDP Issues Two Enforcement Letters in September Citing Risk Information

J.W. Schomisch
September 30, 2019 at 12:44 PM EST
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The FDA’s Office of Prescription Drug Promotion (OPDP) sent out two enforcement letters to companies in September.

The agency sent a Sept. 13 Warning Letter to Galt Pharmaceuticals in Atlanta, over a professional e-mail for Doral (quazepam) tablets for oral use and a Sept. 24 Untitled Letter to Kowa Pharmaceuticals America, Inc., in Montgomery, Ala., over a direct-to-consumer patient testimonial video montage on YouTube for Livalo (pitavastatin) tablet for oral use.

“These latest FDA enforcement letters are especially important and interesting, in that they reflect a focus on information shared through a YouTube video posted on the Internet, as well as an apparent failure to take seriously a prior FDA warning about inappropriate messaging,” stated Jon Bigelow, executive director of the Coalition for Healthcare Communication.

In the Warning Letter, OPDP alleged the Galt “email makes false or misleading claims and/or representations about the risks associated with and efficacy of Doral.”

OPDP noted that it had expressed concerns regarding promotional materials for Doral in an Oct. 29, 2014, Untitled Letter to Sciecure Pharma, Inc. regarding a Doral professional sales aid “that omitted important risk information, contained unsubstantiated superiority claims, and omitted material facts. While Sciecure is no longer the application holder, OPDP is concerned that Galt is continuing to promote this product in a similarly violative manner.”

“The email includes numerous claims and presentations regarding the benefits of using Doral for the treatment of insomnia. However, it completely omits the warning and precaution regarding benzodiazepine withdrawal syndrome. Additionally, while the email presents some risk information regarding the serious risks associated with Doral, it omits certain material information pertaining to these risks.”

OPDP alleged the email failed to disclose information from the Warnings and Precautions, CNS-Depressant Effects and Daytime Impairment section of the package insert that patients should be cautioned against driving or engaging in other hazardous activities or activities requiring complete mental alertness, that downward dose adjustment of Doral and concomitant CNS depressants should be considered, that use of Doral with other sedative hypnotics is not recommended, and that there is an increased risk of next-day psychomotor impairment if Doral is taken with less than a full night of sleep remaining (7 to 8 hours).

OPDP also alleged the email failed to disclose material information from the Severe Anaphylactic and Anaphylactoid Reactions section that some patients have required medical therapy in the emergency department, if angioedema involves the tongue, glottis or larynx, airway obstruction may occur and be fatal, and that patients who develop angioedema after treatment with Doral should not be rechallenged.

OPDP also contended the email failed to disclose material information from the Abnormal Thinking and Behavior Changes section regarding the types of behavior changes and some complex behaviors that may occur, as well as information about discontinuing Doral if “sleep-driving” occurs.

OPDP also alleged the email failed to disclose material information from the Worsening of Depression section regarding appropriate precautions that should be considered in this patient population (e.g., limiting the total prescription size and increased monitoring for suicidal ideation).

Email Warning Statement Is Not Enough

OPDP acknowledged the email included the statement: “For a full list of warnings and precautions, please refer to the full prescribing information.” “However, this does not mitigate the omission of the aforementioned risk information from the email. By omitting this material information related to serious risks associated with the drug, the email, similar to the professional sales aid at issue in the 2014 Untitled Letter, misleadingly suggests that Doral is safer than has been demonstrated,” the Warning Letter said.

The Warning Letter noted the email included several claims under a bolded header – “Concerned about Abuse potential of sleep medications?”:

  • “Doral’s relative likelihood of abuse is considerably lower than some of the widely used sleep aids (i.e., Zolpidem & Temazepam)”;
  • “Doral was ranked even lower than OTC product Diphenhydramine for relative abuse potential”;
  • A figure comparing the “Relative Likelihood of Abuse” of 19 drugs, with Quazepam shown as having a score lower than 16 of the drugs depicted;
  • “Doral’s abuse potential is 1/2 of Zolpidem & 1/3 of Temazepam.”

“These claims and presentation are misleading because they minimize the risks of abuse and dependence associated with Doral and suggest that this C-IV scheduled drug is superior in safety to other prescription and over-the-counter (OTC) products,” the Warning Letter said.

OPDP said the cited reference for the claims “provides an algorithm that purportedly differentiates the likelihood of abuse and relative toxicity among 19 compounds, including Doral (quazepam). However, as FDA pointed out in 2014, ‘the “algorithm” lacks actual abuse data in human subjects and has not been validated.’”

And while the figure includes the statement – “Please see complete prescribing information for detailed information on each product. The above chart is not intended for efficacy comparison. The authors’ algorithm, while comprehensive, does lack prospective abuse data in human subjects and had not been validated in subsequent research,” – the “statement does not mitigate the overwhelming impression that Doral is superior in safety to other prescription and OTC products,” the Warning Letter said.

“Furthermore, this misleading impression is compounded by the fact that the email fails to disclose Doral’s potential for abuse and dependence, including that Doral is classified as a schedule IV-controlled substance,” OPDP said. “This is alarming as it appears that Galt is intentionally attempting to promote Doral as a non-controlled product that is safer than over-the-counter medication.”

The Warning Letter also said the email includes a claim that “Doral is the only marketed medication for Insomnia that helps with all three important components of sleep: difficulty falling asleep; difficulty staying asleep; and early morning awakening.” “This claim is false because it suggests that Doral is the only marketed medication indicated for the treatment of insomnia characterized by difficulty falling asleep, frequent nocturnal awakenings, and/or early morning awakenings. However, there are other marketed medications indicated for all three of these components of sleep,” the Warning Letter said.

The email also included claims about the use of Doral such as:

  • “For your patients with insomnia, Prescribe Doral (Quazepam) for a complete night’s sleep”; and
  • “Doral (Quazepam) is indicated for the treatment of insomnia characterized by difficulty falling asleep, frequent nocturnal awakenings, and/or early morning awakenings.”

“These claims are misleading because the email omits material information from the Indications and Usage section of the PI: ‘Because insomnia is often transient and intermittent, the prolonged administration of DORAL Tablets is generally not necessary or recommended. Since insomnia may be a symptom of several other disorders, the possibility that the complaint may be related to a condition for which there is a more specific treatment should be considered.’ By omitting this information, the email creates a misleading impression about the use of Doral.”

OPDP added the “omissions are particularly concerning from a public health perspective due to the serious health risks associated with Doral that should be considered when prescribing the product.”

OPDP requested the company “immediately cease misbranding Doral and/or cease introducing the misbranded drug into interstate commerce.” The agency also requested a written response stating whether the company intended to comply with the request, which included a listing of all promotional materials (with the 2253 submission dates) for Doral that contained similar statements and a plan for discontinuing the use of such materials, or, in the alternative, for ceasing distribution of Doral.

“Because the violations are serious and repeated, we request, further, that your submission include a comprehensive plan of action to disseminate truthful, non-misleading, and complete corrective messages about the issues discussed in this letter to the audience(s) that received the violative promotional materials,” the Warning Letter said.

OPDP recommended that the corrective piece(s) include a description of the violative promotional piece(s) and/or activity, include a summary of the violative message(s), provide information to correct each of the violative message(s), and be free of promotional claims and presentations. The agency added the corrective messaging should be distributed using the same media, and generally for the same duration of time and with the same frequency that the violative promotional material was disseminated.

The Warning Letter added that if the company believed its products were not in violation of the FD&C Act, it should include its reasoning and any supporting information for OPDP consideration in the response.

Livalo Video Also Deemphasizes Risks

In the Untitled Letter to Kowa Pharmaceuticals, OPDP said the YouTube video for Livalo “is concerning from a public health perspective because it creates a misleading impression regarding the side effects a patient may experience as a result of Livalo treatment and deemphasizes the risks associated with taking the drug. … The video is especially concerning given that Livalo is associated with a number of serious risks, including the risk of skeletal muscle effects.”

The Untitled Letter contended the video “misleadingly suggests that Livalo is safer than its competitors by implying that patients switching to Livalo from other statins will experience a reduction in side effects compared to other statins, or no side effects at all.”

OPDP noted that “while the patient testimonials in this presentation may be an accurate reflection of these patients’ own personal experiences with Livalo, the testimonials do not adequately support the suggestion in the presentation that other patients switching to Livalo from other statins will experience a similar reduction in side effects compared to other statins, or no side effects at all.”

Although  the video includes a superimposed statement that “Individual results may vary,” OPDP said the statement “does not mitigate the misleading impression from the presentation. FDA is not aware of any data to support the suggestion that patients switching to Livalo from other statins will experience a reduction in side effects compared to other statins, or no side effects at all. If you have data to support this suggestion, please submit them to FDA for review,” the Untitled Letter said.

OPDP also contended the video is “misleading because it fails to present information relating to contraindications, warnings, precautions and adverse reactions for Livalo with a prominence and readability reasonably comparable with the presentation of information relating to the benefits of Livalo.”

The Untitled Letter noted “benefit claims for Livalo are presented prominently as part of the patient testimonials, which encompass the majority of the screen throughout the video. However, the risk information is presented as scrolling text relegated to the bottom of the video during these patient testimonials. The patient testimonials also compete for the consumers’ attention making it difficult for them to adequately process and comprehend the risk information. The overall effect of disclosing risk information in this manner as scrolling text relegated to the bottom of the video, along with the simultaneous presentation of the patient testimonials, undermines the communication of risk information and thereby misleadingly minimized the risks associated with the use of Livalo.”

OPDP requested the company “immediately cease violating the FD&C Act” and submit a written response indicating whether the company will comply with the request and provide a listing of all promotional materials (with the 2253 submission dates) for Livalo that contain the cited violations, as well as a plan for discontinuing the use of the violative materials.

The Untitled Letter added that if the company believed its products were not in violation of the FD&C Act, it should include its reasoning and any supporting information for OPDP consideration in the response.

To date, OPDP has issued two Warning Letters and five Untitled Letters in 2019, which is the same as the agency issued in 2018. OPDP issued three Warning Letters and two Untitled Letters in 2017.

Editor’s note: All FDA Warning and Untitled Letters are available in Thompson Information Services’ FDA Enforcement Letter Database, which is available to subscribers of Thompson's FDA Compliance Expert.

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